19-10994926-G-T

Position:

• chr19-10994926-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000344626.10(SMARCA4):​c.1518G>T​(p.Thr506Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 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 (★). Synonymous variant affecting the same amino acid position (i.e. T506T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 ENST00000344626.10 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.71

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-10994926-G-T is Benign according to our data. Variant chr19-10994926-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1558351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.71 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1518G>T	p.Thr506Thr	synonymous_variant	9/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1518G>T	p.Thr506Thr	synonymous_variant	9/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1518G>T	p.Thr506Thr	synonymous_variant	9/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1518G>T	p.Thr506Thr	synonymous_variant	9/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1518G>T	p.Thr506Thr	synonymous_variant	9/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1518G>T	p.Thr506Thr	synonymous_variant	10/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1518G>T	p.Thr506Thr	synonymous_variant	9/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1518G>T	p.Thr506Thr	synonymous_variant	9/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1518G>T	p.Thr506Thr	synonymous_variant	10/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.930G>T	p.Thr310Thr	synonymous_variant	6/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.162G>T	p.Thr54Thr	synonymous_variant	2/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.246G>T	p.Thr82Thr	synonymous_variant	2/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.6G>T	p.Thr2Thr	synonymous_variant	1/27			ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251332 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.12
DANN	Benign	0.78

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: rs145369952; hg19: chr19-11105602;