19-11060093-A-G

Position:

• chr19-11060093-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003072.5(SMARCA4):​c.4817A>G​(p.Gln1606Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,400,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 1.09

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 Likely_benign. Variant got -5 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). 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08920765).
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4913A>G	p.Gln1638Arg	missense_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4817A>G	p.Gln1606Arg	missense_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4913A>G	p.Gln1638Arg	missense_variant	35/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4817A>G	p.Gln1606Arg	missense_variant	34/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4823A>G	p.Gln1608Arg	missense_variant	34/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4727A>G	p.Gln1576Arg	missense_variant	34/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4727A>G	p.Gln1576Arg	missense_variant	33/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4727A>G	p.Gln1576Arg	missense_variant	33/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4724A>G	p.Gln1575Arg	missense_variant	34/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4238A>G	p.Gln1413Arg	missense_variant	31/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3467A>G	p.Gln1156Arg	missense_variant	27/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3449A>G	p.Gln1150Arg	missense_variant	26/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3311A>G	p.Gln1104Arg	missense_variant	26/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3077A>G	p.Gln1026Arg	missense_variant	24/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.881A>G	p.Gln294Arg	missense_variant	7/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000128 AC: 2 AN: 156396 Hom.: 0 AF XY: 0.0000242 AC XY: 2 AN XY: 82692

Gnomad AFR exome AF: 0.000118

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: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000264 AC: 37 AN: 1400658 Hom.: 0 Cov.: 33 AF XY: 0.0000246 AC XY: 17 AN XY: 691010

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: 0.0000333

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1638 of the SMARCA4 protein (p.Gln1638Arg). 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: 238491). 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	Feb 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 28, 2023	The SMARCA4 c.4913A>G (p.Gln1638Arg) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with rhabdoid tumor predisposition syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 30, 2024	The SMARCA4 c.4913A>G (p.Gln1638Arg) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.000013 (2/156396 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	GeneDx	Dec 22, 2023	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 -

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;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

May 15, 2024

- -

SMARCA4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

The SMARCA4 c.4913A>G variant is predicted to result in the amino acid substitution p.Gln1638Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 2 of ~156,000 alleles in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/238491/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.28	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.51	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.75	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.097	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.062
MutPred		0.14		.;.;Gain of methylation at R1640 (P = 0.0508);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at R1640 (P = 0.0508);.;.;.;.;
MVP		0.60
MPC		1.1
ClinPred		0.11	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.57

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: rs878854231; hg19: chr19-11170769;