19-11058324-C-T

Position:

• chr19-11058324-C-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.4494C>T​(p.Tyr1498Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,613,332 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.54

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 19-11058324-C-T is Benign according to our data. Variant chr19-11058324-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00395 (602/152252) while in subpopulation AFR AF= 0.0138 (573/41538). AF 95% confidence interval is 0.0129. There are 3 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 602 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4590C>T	p.Tyr1530Tyr	synonymous_variant	32/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4494C>T	p.Tyr1498Tyr	synonymous_variant	31/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4590C>T	p.Tyr1530Tyr	synonymous_variant	32/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4494C>T	p.Tyr1498Tyr	synonymous_variant	31/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4500C>T	p.Tyr1500Tyr	synonymous_variant	31/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4404C>T	p.Tyr1468Tyr	synonymous_variant	31/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4404C>T	p.Tyr1468Tyr	synonymous_variant	30/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4404C>T	p.Tyr1468Tyr	synonymous_variant	30/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4401C>T	p.Tyr1467Tyr	synonymous_variant	31/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3915C>T	p.Tyr1305Tyr	synonymous_variant	28/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3144C>T	p.Tyr1048Tyr	synonymous_variant	24/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3126C>T	p.Tyr1042Tyr	synonymous_variant	23/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2988C>T	p.Tyr996Tyr	synonymous_variant	23/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2856C>T	p.Tyr952Tyr	synonymous_variant	22/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.660C>T	p.Tyr220Tyr	synonymous_variant	5/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152134 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000992 AC: 249 AN: 251050 Hom.: 1 AF XY: 0.000707 AC XY: 96 AN XY: 135844

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000363 AC: 531 AN: 1461080 Hom.: 1 Cov.: 32 AF XY: 0.000305 AC XY: 222 AN XY: 726876

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00395 AC: 602 AN: 152252 Hom.: 3 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74450

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00211 Hom.: 1

Bravo AF: 0.00450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	This alteration is classified as 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. -

Intellectual disability, autosomal dominant 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Coffin-Siris syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.5
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139505007; hg19: chr19-11169000;