rs1064795842

Positions:

• chr19-10986922-A-C
• chr19-10986922-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_003072.5(SMARCA4):​c.778A>C​(p.Met260Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,268 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 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 8.38

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 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.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000395 (6/152016) while in subpopulation NFE AF= 0.0000883 (6/67974). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 2 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
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.778A>C	p.Met260Leu	missense_variant	5/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.778A>C	p.Met260Leu	missense_variant	5/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.778A>C	p.Met260Leu	missense_variant	5/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.778A>C	p.Met260Leu	missense_variant	5/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.778A>C	p.Met260Leu	missense_variant	5/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.778A>C	p.Met260Leu	missense_variant	6/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.778A>C	p.Met260Leu	missense_variant	5/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.778A>C	p.Met260Leu	missense_variant	5/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.778A>C	p.Met260Leu	missense_variant	6/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.190A>C	p.Met64Leu	missense_variant	2/32			ENSP00000496004.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250088 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135364

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1460252 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 726518

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: 0.0000414

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74256

Gnomad4 AFR AF: 0.00

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: 0.0000883

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 04, 2024	The SMARCA4 c.778A>C (p.Met260Leu) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.00004 (2/50380 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27930734) -

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 260 of the SMARCA4 protein (p.Met260Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 422533). 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	Sep 19, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2021	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. -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Benign	0.85
DEOGEN2	Benign	0.28	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.049
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.78	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.62	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.93	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0020	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.47
MutPred		0.27		Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);Gain of catalytic residue at M260 (P = 0.0446);
MVP		0.90
MPC		0.24
ClinPred		0.79	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.29
gMVP		0.033

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: rs1064795842; hg19: chr19-11097598;