rs878854197

Variant names:

• chr19-10987915-G-A
• rs878854197
• NM_001387283.1:c.1109G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10987915-G-A
• chr19-10987915-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001387283.1(SMARCA4):​c.1109G>A​(p.Arg370His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R370C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.81
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1109G>A	p.Arg370His	missense_variant	Exon 7 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1109G>A	p.Arg370His	missense_variant	Exon 6 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1109G>A	p.Arg370His	missense_variant	Exon 7 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.521G>A	p.Arg174His	missense_variant	Exon 3 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 240626 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460470 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5242

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.009554), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 370 of the SMARCA4 protein (p.Arg370His). 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: 238362). 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 expected to disrupt SMARCA4 protein function with a positive 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R370H variant (also known as c.1109G>A), located in coding exon 5 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1109. The arginine at codon 370 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.84
MutPred		0.45		Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);
MVP		0.91
MPC		2.6
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.85
gMVP		0.87
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs878854197; hg19: chr19-11098591; COSMIC: COSV60792852;