19-10986198-C-A

Position:

• chr19-10986198-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003072.5(SMARCA4):​c.365C>A​(p.Ser122*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-10986198-C-A is Pathogenic according to our data. Variant chr19-10986198-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 861042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.365C>A	p.Ser122*	stop_gained	4/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.365C>A	p.Ser122*	stop_gained	4/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.365C>A	p.Ser122*	stop_gained	4/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.365C>A	p.Ser122*	stop_gained	4/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.365C>A	p.Ser122*	stop_gained	4/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.365C>A	p.Ser122*	stop_gained	5/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.365C>A	p.Ser122*	stop_gained	4/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.365C>A	p.Ser122*	stop_gained	4/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.365C>A	p.Ser122*	stop_gained	5/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461462 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser122*) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.95
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs1555752859; hg19: chr19-11096874; COSMIC: COSV60808027; COSMIC: COSV60808027;