19-11024378-C-T

Variant names:

• chr19-11024378-C-T
• rs1555780015
• NM_001387283.1:c.3021C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003072.5(SMARCA4):​c.3021C>T​(p.Leu1007Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1007L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.501

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-11024378-C-T is Benign according to our data. Variant chr19-11024378-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436809.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 22 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 21 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3021C>T	p.Leu1007Leu	synonymous_variant	Exon 22 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2433C>T	p.Leu811Leu	synonymous_variant	Exon 18 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1665C>T	p.Leu555Leu	synonymous_variant	Exon 14 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1746C>T	p.Leu582Leu	synonymous_variant	Exon 14 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1506C>T	p.Leu502Leu	synonymous_variant	Exon 13 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1374C>T	p.Leu458Leu	synonymous_variant	Exon 12 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

May 01, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Sep 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.3
DANN	Benign	0.74

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: rs1555780015; hg19: chr19-11135054;