NM_001387283.1:c.4399G>A

Variant names:

• chr19-11041439-G-A
• rs796506759
• NM_001387283.1:c.4399G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001387283.1(SMARCA4):​c.4399G>A​(p.Asp1467Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 9.95

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36362296).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4399G>A	p.Asp1467Asn	missense_variant	Exon 31 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4303G>A	p.Asp1435Asn	missense_variant	Exon 30 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4399G>A	p.Asp1467Asn	missense_variant	Exon 31 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4303G>A	p.Asp1435Asn	missense_variant	Exon 30 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4309G>A	p.Asp1437Asn	missense_variant	Exon 30 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4213G>A	p.Asp1405Asn	missense_variant	Exon 30 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4213G>A	p.Asp1405Asn	missense_variant	Exon 29 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4213G>A	p.Asp1405Asn	missense_variant	Exon 29 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4213G>A	p.Asp1405Asn	missense_variant	Exon 30 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3724G>A	p.Asp1242Asn	missense_variant	Exon 27 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2956G>A	p.Asp986Asn	missense_variant	Exon 23 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2938G>A	p.Asp980Asn	missense_variant	Exon 22 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2797G>A	p.Asp933Asn	missense_variant	Exon 22 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2665G>A	p.Asp889Asn	missense_variant	Exon 21 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.469G>A	p.Asp157Asn	missense_variant	Exon 4 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460282 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726504

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:2

Jul 22, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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:2

May 23, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1467 of the SMARCA4 protein (p.Asp1467Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMARCB1-related conditions (PMID: 37500730). ClinVar contains an entry for this variant (Variation ID: 470399). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

not specified Uncertain:1

Mar 11, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Apr 26, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.037	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;T;D;.;.;.;.;.
Polyphen		0.80	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.32
MutPred		0.27		.;.;Gain of loop (P = 0.0045);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of loop (P = 0.0045);.;.;.;.;.;
MVP		0.79
MPC		1.5
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.21
gMVP		0.66

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: rs796506759; hg19: chr19-11152115; COSMIC: COSV105909492; COSMIC: COSV105909492;