19-10986463-G-T

Position:

chr19-10986463-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_003072.5(SMARCA4):c.630G>T(p.Met210Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000514 in 1,556,854 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.53

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ: 6.8459 (greater than the threshold 3.09). Trascript score misZ: 8.7957 (greater than threshold 3.09). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.26705486).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.630G>T	p.Met210Ile	missense_variant	4/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.630G>T	p.Met210Ile	missense_variant	4/35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.630G>T	p.Met210Ile	missense_variant	4/36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.630G>T	p.Met210Ile	missense_variant	4/35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.630G>T	p.Met210Ile	missense_variant	4/35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.630G>T	p.Met210Ile	missense_variant	5/35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.630G>T	p.Met210Ile	missense_variant	4/34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.630G>T	p.Met210Ile	missense_variant	4/34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.630G>T	p.Met210Ile	missense_variant	5/35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.42G>T	p.Met14Ile	missense_variant	1/32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

156832

Hom.:

AF XY:

0.00

AC XY:

AN XY:

84268

show subpopulations

Gnomad AFR exome

AF:

0.000115

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000498

AC:

AN:

1404618

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

693668

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000554

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 210 of the SMARCA4 protein (p.Met210Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 537788). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

Eigen

Benign

0.034

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.6

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

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.47

Sift

Benign

0.046

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

Sift4G

Benign

0.26

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

Polyphen

0.21

B;.;P;.;.;.;.;.;.;.;B;.;.;.;.;.;.;P

Vest4

0.43

MutPred

0.29

Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);Loss of glycosylation at P211 (P = 0.0853);

MVP

0.65

MPC

0.49

ClinPred

0.32

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over