19-11023625-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001387283.1(SMARCA4):c.2967C>T(p.Pro989Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,603,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -5.46

Publications

1 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 19-11023625-C-T is Benign according to our data. Variant chr19-11023625-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212247.

BP7

Synonymous conserved (PhyloP=-5.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000473 (72/152314) while in subpopulation AFR AF = 0.00161 (67/41574). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 21 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 20 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.2967C>T	p.Pro989Pro	synonymous_variant	Exon 21 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.2379C>T	p.Pro793Pro	synonymous_variant	Exon 17 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.1611C>T	p.Pro537Pro	synonymous_variant	Exon 13 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.1692C>T	p.Pro564Pro	synonymous_variant	Exon 13 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.1452C>T	p.Pro484Pro	synonymous_variant	Exon 12 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.1320C>T	p.Pro440Pro	synonymous_variant	Exon 11 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000188

AC:

AN:

239298

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.0000597

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000896

AC:

130

AN:

1451414

Hom.:

Cov.:

AF XY:

0.0000790

AC XY:

AN XY:

721758

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

33310

American (AMR)

AF:

0.000137

AC:

AN:

43938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.000101

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52862

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000326

AC:

AN:

1105006

Other (OTH)

AF:

0.000250

AC:

AN:

60030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000473

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000290

Hom.:

Bravo

AF:

0.000601

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Dec 22, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 14, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

not specified

Uncertain:1

May 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 16

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 20, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SMARCA4-related disorder

Benign:1

Feb 08, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.7

(source)

DANN

Benign

0.66

PhyloP100

-5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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