NM_001387283.1:c.3703G>A

Variant names:

• chr19-11033446-G-A
• rs759192892
• NM_001387283.1:c.3703G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001387283.1(SMARCA4):​c.3703G>A​(p.Asp1235Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.61

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 27 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 27 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3115G>A	p.Asp1039Asn	missense_variant	Exon 23 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2347G>A	p.Asp783Asn	missense_variant	Exon 19 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2428G>A	p.Asp810Asn	missense_variant	Exon 19 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2188G>A	p.Asp730Asn	missense_variant	Exon 18 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2056G>A	p.Asp686Asn	missense_variant	Exon 17 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.-42G>A		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251040 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461024 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726800

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces aspartic acid with asparagine at codon 1235 of the SMARCA4 protein (p.Asp1235Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs759192892, ExAC 0.006%). This variant has not been reported in the literature in individuals with SMARCA4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1235N variant (also known as c.3703G>A), located in coding exon 25 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 3703. The aspartic acid at codon 1235 is replaced by asparagine, 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. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). 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	0.92
BayesDel_addAF	Benign	-0.00057	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.17	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.024	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Uncertain	0.024	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.
Polyphen		0.068	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.80
MutPred		0.58		Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);.;Loss of ubiquitination at K1237 (P = 0.0272);.;.;.;
MVP		0.92
MPC		1.5
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.41
gMVP		0.94

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: rs759192892; hg19: chr19-11144122;