19-11033775-C-T

Variant names:

• chr19-11033775-C-T
• rs797045985
• NM_001387283.1:c.3783C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001387283.1(SMARCA4):​c.3783C>T​(p.His1261His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 627,754 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.03
• 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

ENSG00000278643 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-11033775-C-T is Benign according to our data. Variant chr19-11033775-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 470368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000319 (2/627754) while in subpopulation MID AF = 0.000482 (2/4148). AF 95% confidence interval is 0.0000849. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 2. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3783C>T	p.His1261His	synonymous_variant	Exon 27 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3783C>T	p.His1261His	synonymous_variant	Exon 27 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3783C>T	p.His1261His	synonymous_variant	Exon 27 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3783C>T	p.His1261His	synonymous_variant	Exon 27 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643995.1	c.3195C>T	p.His1065His	synonymous_variant	Exon 24 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2427C>T	p.His809His	synonymous_variant	Exon 20 of 28			ENSP00000495599.1
SMARCA4	ENST00000642350.1	c.2268C>T	p.His756His	synonymous_variant	Exon 19 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2136C>T	p.His712His	synonymous_variant	Exon 18 of 25			ENSP00000494159.1
SMARCA4	ENST00000643549.1	c.3774+258C>T		intron_variant	Intron 26 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3774+258C>T		intron_variant	Intron 27 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3774+258C>T		intron_variant	Intron 26 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3774+258C>T		intron_variant	Intron 26 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3774+258C>T		intron_variant	Intron 27 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000644065.1	c.2499+258C>T		intron_variant	Intron 19 of 26			ENSP00000493615.1
SMARCA4	ENST00000538456.4	c.30+258C>T		intron_variant	Intron 1 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000319 AC: 2 AN: 627754 Hom.: 0 Cov.: 2 AF XY: 0.00000585 AC XY: 2 AN XY: 342030

African (AFR) AF: 0.00 AC: 0 AN: 17704

American (AMR) AF: 0.00 AC: 0 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20990

East Asian (EAS) AF: 0.00 AC: 0 AN: 36070

South Asian (SAS) AF: 0.00 AC: 0 AN: 69804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51902

Middle Eastern (MID) AF: 0.000482 AC: 2 AN: 4148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 350312

Other (OTH) AF: 0.00 AC: 0 AN: 33090

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 30, 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
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.74
PhyloP100		1.0
PromoterAI		0.032	Neutral
Mutation Taster		=100/0	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: rs797045985; hg19: chr19-11144451;