19-11034152-C-T

Position:

• chr19-11034152-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003072.5(SMARCA4):​c.3903C>T​(p.Thr1301Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,812 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: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -9.84

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-11034152-C-T is Benign according to our data. Variant chr19-11034152-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000269 (41/152302) while in subpopulation AFR AF= 0.00089 (37/41562). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3903C>T	p.Thr1301Thr	synonymous_variant	28/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3903C>T	p.Thr1301Thr	synonymous_variant	28/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3903C>T	p.Thr1301Thr	synonymous_variant	28/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3903C>T	p.Thr1301Thr	synonymous_variant	28/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3804C>T	p.Thr1268Thr	synonymous_variant	27/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3804C>T	p.Thr1268Thr	synonymous_variant	28/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3804C>T	p.Thr1268Thr	synonymous_variant	27/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3804C>T	p.Thr1268Thr	synonymous_variant	27/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3804C>T	p.Thr1268Thr	synonymous_variant	28/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3315C>T	p.Thr1105Thr	synonymous_variant	25/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2547C>T	p.Thr849Thr	synonymous_variant	21/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2529C>T	p.Thr843Thr	synonymous_variant	20/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2388C>T	p.Thr796Thr	synonymous_variant	20/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2256C>T	p.Thr752Thr	synonymous_variant	19/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.60C>T	p.Thr20Thr	synonymous_variant	2/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251088 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135842

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461510 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727072

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74468

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SMARCA4: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2022	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2015	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2020	- -

Rhabdoid tumor predisposition syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

SMARCA4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs147314370; hg19: chr19-11144828;