19-11003076-C-T

Variant names:

• chr19-11003076-C-T
• rs141751028
• NM_001387283.1:c.1860C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_003072.5(SMARCA4):​c.1860C>T​(p.Ile620Ile) 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.793
• Publications: 0 publications found

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]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 19-11003076-C-T is Benign according to our data. Variant chr19-11003076-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3233078.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.793 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 13 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 12 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 13 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1272C>T	p.Ile424Ile	synonymous_variant	Exon 9 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.504C>T	p.Ile168Ile	synonymous_variant	Exon 5 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.585C>T	p.Ile195Ile	synonymous_variant	Exon 5 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.345C>T	p.Ile115Ile	synonymous_variant	Exon 4 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.213C>T	p.Ile71Ile	synonymous_variant	Exon 3 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Jan 30, 2024

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	-0.20
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.79
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs141751028; hg19: chr19-11113752; COSMIC: COSV60805978; COSMIC: COSV60805978;