rs1060502070

Positions:

• chr19-11035083-G-A
• chr19-11035083-G-C
• chr19-11035083-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_003072.5(SMARCA4):​c.4121G>A​(p.Arg1374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.87

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.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4121G>A	p.Arg1374His	missense_variant	29/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4121G>A	p.Arg1374His	missense_variant	29/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4121G>A	p.Arg1374His	missense_variant	29/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4121G>A	p.Arg1374His	missense_variant	29/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4022G>A	p.Arg1341His	missense_variant	28/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4022G>A	p.Arg1341His	missense_variant	29/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4022G>A	p.Arg1341His	missense_variant	28/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4022G>A	p.Arg1341His	missense_variant	28/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4022G>A	p.Arg1341His	missense_variant	29/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3533G>A	p.Arg1178His	missense_variant	26/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2765G>A	p.Arg922His	missense_variant	22/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2747G>A	p.Arg916His	missense_variant	21/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2606G>A	p.Arg869His	missense_variant	21/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2474G>A	p.Arg825His	missense_variant	20/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.278G>A	p.Arg93His	missense_variant	3/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460654 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726642

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1374 of the SMARCA4 protein (p.Arg1374His). 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: 408624). 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. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2022

The p.R1374H variant (also known as c.4121G>A), located in coding exon 28 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4121. The arginine at codon 1374 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.027	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.059	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.94	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.;.
Vest4		0.76
MutPred		0.58		Loss of MoRF binding (P = 0.0446);.;Loss of MoRF binding (P = 0.0446);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0446);.;.;.;.;.;.;Loss of MoRF binding (P = 0.0446);.;.;.;.;.;
MVP		0.93
MPC		3.1
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.35
gMVP		0.86

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: rs1060502070; hg19: chr19-11145759; COSMIC: COSV60795258; COSMIC: COSV60795258;