19-10986422-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001387283.1(SMARCA4):c.589C>T(p.Pro197Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,577,668 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 16 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 7.83

Publications

19 publications found

Variant links:

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008630902).

BP6

Variant 19-10986422-C-T is Benign according to our data. Variant chr19-10986422-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00192 (293/152328) while in subpopulation SAS AF = 0.00538 (26/4830). AF 95% confidence interval is 0.00377. There are 1 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 5 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 4 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.589C>T	p.Pro197Ser	missense_variant	Exon 5 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.1C>T	p.Pro1Ser	missense_variant	Exon 1 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00291

AC:

535

AN:

183762

AF XY:

0.00310

show subpopulations

Gnomad AFR exome

AF:

0.0000923

Gnomad AMR exome

AF:

0.000221

Gnomad ASJ exome

AF:

0.000797

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00943

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00205

GnomAD4 exome

AF:

0.00195

AC:

2773

AN:

1425340

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1504

AN XY:

705808

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32802

American (AMR)

AF:

0.000234

AC:

AN:

38386

Ashkenazi Jewish (ASJ)

AF:

0.000708

AC:

AN:

25418

East Asian (EAS)

AF:

0.00

AC:

AN:

37892

South Asian (SAS)

AF:

0.00718

AC:

589

AN:

82052

European-Finnish (FIN)

AF:

0.0101

AC:

500

AN:

49674

Middle Eastern (MID)

AF:

0.00471

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00139

AC:

1526

AN:

1094338

Other (OTH)

AF:

0.00174

AC:

103

AN:

59044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152328

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41584

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00538

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

68030

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00157

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.00249

AC:

298

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMARCA4: PP2, BS2 -

Sep 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18437052, 24728327, 22407764, 26744134, 11085541) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jul 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 16

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

May 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Coffin-Siris syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

1.0

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.18

T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T

Sift4G

Benign

0.36

T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T

Polyphen

1.0

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D

Vest4

0.78

MVP

0.66

MPC

0.91

ClinPred

0.036

GERP RS

4.3

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.13

gMVP

0.62

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over