NM_001387283.1:c.2388C>T

Variant names:

• chr19-11013062-C-T
• rs28997580
• NM_001387283.1:c.2388C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001387283.1(SMARCA4):​c.2388C>T​(p.Leu796Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,614,174 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 32)
  • Exomes 𝑓: 0.010 (174 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.01

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]

ENSG00000266936 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-11013062-C-T is Benign according to our data. Variant chr19-11013062-C-T is described in ClinVar as [Benign]. Clinvar id is 220858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11013062-C-T is described in Lovd as [Likely_benign]. Variant chr19-11013062-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00664 (1011/152340) while in subpopulation SAS AF= 0.0524 (253/4832). AF 95% confidence interval is 0.0471. There are 12 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 17 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 16 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2388C>T	p.Leu796Leu	synonymous_variant	Exon 17 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1800C>T	p.Leu600Leu	synonymous_variant	Exon 13 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1032C>T	p.Leu344Leu	synonymous_variant	Exon 9 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1113C>T	p.Leu371Leu	synonymous_variant	Exon 9 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.873C>T	p.Leu291Leu	synonymous_variant	Exon 8 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.741C>T	p.Leu247Leu	synonymous_variant	Exon 7 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1012 AN: 152222 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00876

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0106 AC: 2667 AN: 251418 Hom.: 50 AF XY: 0.0125 AC XY: 1694 AN XY: 135898

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0497

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00996 AC: 14560 AN: 1461834 Hom.: 174 Cov.: 31 AF XY: 0.0109 AC XY: 7917 AN XY: 727218

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0453

Gnomad4 FIN exome AF: 0.00358

Gnomad4 NFE exome AF: 0.00865

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.00664 AC: 1011 AN: 152340 Hom.: 12 Cov.: 32 AF XY: 0.00695 AC XY: 518 AN XY: 74490

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0524

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00875

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00660 Hom.: 2

Bravo AF: 0.00503

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00670

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 12, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Intellectual disability, autosomal dominant 16 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 18, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

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	-0.32
CADD	Benign	11
DANN	Benign	0.90

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: rs28997580; hg19: chr19-11123738; COSMIC: COSV104418424; COSMIC: COSV104418424;