19-11041385-A-G

Variant names:

• chr19-11041385-A-G
• rs373390083
• NM_001387283.1:c.4345A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_003072.5(SMARCA4):​c.4249A>G​(p.Ser1417Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.06251553).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000263 (4/152220) while in subpopulation AFR AF= 0.0000965 (4/41450). AF 95% confidence interval is 0.0000325. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4345A>G	p.Ser1449Gly	missense_variant	Exon 31 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4249A>G	p.Ser1417Gly	missense_variant	Exon 30 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4345A>G	p.Ser1449Gly	missense_variant	Exon 31 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4249A>G	p.Ser1417Gly	missense_variant	Exon 30 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4255A>G	p.Ser1419Gly	missense_variant	Exon 30 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4159A>G	p.Ser1387Gly	missense_variant	Exon 30 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4159A>G	p.Ser1387Gly	missense_variant	Exon 29 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4159A>G	p.Ser1387Gly	missense_variant	Exon 29 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4159A>G	p.Ser1387Gly	missense_variant	Exon 30 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3670A>G	p.Ser1224Gly	missense_variant	Exon 27 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2902A>G	p.Ser968Gly	missense_variant	Exon 23 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2884A>G	p.Ser962Gly	missense_variant	Exon 22 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2743A>G	p.Ser915Gly	missense_variant	Exon 22 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2611A>G	p.Ser871Gly	missense_variant	Exon 21 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.415A>G	p.Ser139Gly	missense_variant	Exon 4 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.00000403 AC: 1 AN: 248168 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134692

Gnomad AFR exome AF: 0.0000624

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460392 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726574

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.0000965

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

Bravo AF: 0.0000302

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1449 of the SMARCA4 protein (p.Ser1449Gly). This variant is present in population databases (rs373390083, gnomAD 0.007%). 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: 470394). 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. -

Feb 28, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Nov 22, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 02, 2024

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.69	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.34	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.31	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.46	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.12
MVP		0.57
MPC		0.90
ClinPred		0.038	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.62

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

Other links and lift over

dbSNP: rs373390083; hg19: chr19-11152061;