NM_001387283.1:c.1791T>G

Variant names:

• chr19-10996523-T-G
• rs141806282
• NM_001387283.1:c.1791T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001387283.1(SMARCA4):​c.1791T>G​(p.Pro597Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,614,226 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 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.162

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-10996523-T-G is Benign according to our data. Variant chr19-10996523-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212237.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000374 (57/152348) while in subpopulation NFE AF= 0.000647 (44/68030). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 12 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 11 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1791T>G	p.Pro597Pro	synonymous_variant	Exon 12 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1203T>G	p.Pro401Pro	synonymous_variant	Exon 8 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.435T>G	p.Pro145Pro	synonymous_variant	Exon 4 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.516T>G	p.Pro172Pro	synonymous_variant	Exon 4 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.276T>G	p.Pro92Pro	synonymous_variant	Exon 3 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.144T>G	p.Pro48Pro	synonymous_variant	Exon 2 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251496 Hom.: 0 AF XY: 0.000419 AC XY: 57 AN XY: 135922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000624

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000562 AC: 822 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.000562 AC XY: 409 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74502

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.000336

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCA4: BP4, BP7 -

Oct 05, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Jun 15, 2015

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. -

Dec 18, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Uncertain:1

Jun 01, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 Benign:1

Mar 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Coffin-Siris syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.1
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141806282; hg19: chr19-11107199; COSMIC: COSV104654166;