chr19-11034916-C-T

Position:

• chr19-11034916-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_003072.5(SMARCA4):​c.3954C>T​(p.Arg1318Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,409,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.388

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 19-11034916-C-T is Benign according to our data. Variant chr19-11034916-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537797.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	29/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	29/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	29/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3954C>T	p.Arg1318Arg	splice_region_variant, synonymous_variant	29/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	28/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	29/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	28/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	28/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3855C>T	p.Arg1285Arg	splice_region_variant, synonymous_variant	29/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3366C>T	p.Arg1122Arg	splice_region_variant, synonymous_variant	26/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2598C>T	p.Arg866Arg	splice_region_variant, synonymous_variant	22/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2580C>T	p.Arg860Arg	splice_region_variant, synonymous_variant	21/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2439C>T	p.Arg813Arg	splice_region_variant, synonymous_variant	21/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2307C>T	p.Arg769Arg	splice_region_variant, synonymous_variant	20/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.111C>T	p.Arg37Arg	splice_region_variant, synonymous_variant	3/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000568 AC: 8 AN: 1409406 Hom.: 0 Cov.: 32 AF XY: 0.00000574 AC XY: 4 AN XY: 696474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000644

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2025

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2018

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	-0.23
CADD	Benign	17
DANN	Benign	0.88
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555785323; hg19: chr19-11145592;