chr19-11030783-G-T

Position:

• chr19-11030783-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003072.5(SMARCA4):​c.3436G>T​(p.Gly1146Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,610,450 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.99

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Helicase C-terminal (size 162) in uniprot entity SMCA4_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• PM2: Very rare variant in population databases, with high coverage
• 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). GenCC has associacion of 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3436G>T	p.Gly1146Cys	missense_variant	25/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3436G>T	p.Gly1146Cys	missense_variant	25/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3436G>T	p.Gly1146Cys	missense_variant	25/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3436G>T	p.Gly1146Cys	missense_variant	25/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3436G>T	p.Gly1146Cys	missense_variant	25/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3436G>T	p.Gly1146Cys	missense_variant	26/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3436G>T	p.Gly1146Cys	missense_variant	25/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3436G>T	p.Gly1146Cys	missense_variant	25/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3436G>T	p.Gly1146Cys	missense_variant	26/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2848G>T	p.Gly950Cys	missense_variant	22/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2080G>T	p.Gly694Cys	missense_variant	18/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2161G>T	p.Gly721Cys	missense_variant	18/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1921G>T	p.Gly641Cys	missense_variant	17/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1789G>T	p.Gly597Cys	missense_variant	16/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725032

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74496

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

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1146 of the SMARCA4 protein (p.Gly1146Cys). 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: 470352). 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) performed at Invitae 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -

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

Jan 04, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24658002) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

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	0.21
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Uncertain	2.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Uncertain	0.0070	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.
Polyphen		0.98	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.
Vest4		0.54
MVP		0.68
MPC		2.7
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.96

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: rs200007170; hg19: chr19-11141459;