chr19-10986459-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001387283.1(SMARCA4):c.626C>T(p.Pro209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,558,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P209R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.80

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.626C>T	p.Pro209Leu	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.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 5 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 4 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.626C>T	p.Pro209Leu	missense_variant	Exon 5 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.38C>T	p.Pro13Leu	missense_variant	Exon 1 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

159802

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1406492

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

694768

show subpopulations

African (AFR)

AF:

0.0000312

AC:

AN:

32058

American (AMR)

AF:

0.00

AC:

AN:

36384

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25236

East Asian (EAS)

AF:

0.00

AC:

AN:

36410

South Asian (SAS)

AF:

0.00

AC:

AN:

80138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1084240

Other (OTH)

AF:

0.0000171

AC:

AN:

58332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000174

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the SMARCA4 protein (p.Pro209Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 238506). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 19, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

May 23, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMARCA4: BS2 -

Intellectual disability, autosomal dominant 16

Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P209L variant (also known as c.626C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 626. The proline at codon 209 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.6

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

PhyloP100

7.8

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.081

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

Sift4G

Benign

0.085

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

Polyphen

1.0

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

Vest4

0.69

MutPred

0.20

Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);

MVP

0.78

MPC

0.91

ClinPred

0.94

GERP RS

4.3

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.38

Mutation Taster

=17/83

disease causing

(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