19-11033445-C-T

Variant names:

• chr19-11033445-C-T
• rs751373738
• NM_001387283.1:c.3702C>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_003072.5(SMARCA4):​c.3702C>T​(p.Phe1234Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,040 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: 0.000010 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.64

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-11033445-C-T is Benign according to our data. Variant chr19-11033445-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000103 (15/1461040) while in subpopulation EAS AF= 0.000227 (9/39700). AF 95% confidence interval is 0.000118. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 27 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 26 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3702C>T	p.Phe1234Phe	synonymous_variant	Exon 27 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3114C>T	p.Phe1038Phe	synonymous_variant	Exon 23 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2346C>T	p.Phe782Phe	synonymous_variant	Exon 19 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2427C>T	p.Phe809Phe	synonymous_variant	Exon 19 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2187C>T	p.Phe729Phe	synonymous_variant	Exon 18 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2055C>T	p.Phe685Phe	synonymous_variant	Exon 17 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.-43C>T		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251056 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461040 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Apr 26, 2018

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 23, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.6
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs751373738; hg19: chr19-11144121;