19-11030816-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_003072.5(SMARCA4):c.3469C>T(p.Arg1157Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1157G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.41

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain Helicase C-terminal (size 162) in uniprot entity SMCA4_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003072.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11030816-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 19-11030816-C-T is Pathogenic according to our data. Variant chr19-11030816-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2703875.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 26 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 25 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.3469C>T	p.Arg1157Trp	missense_variant	Exon 26 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.2881C>T	p.Arg961Trp	missense_variant	Exon 22 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2113C>T	p.Arg705Trp	missense_variant	Exon 18 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.2194C>T	p.Arg732Trp	missense_variant	Exon 18 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.1954C>T	p.Arg652Trp	missense_variant	Exon 17 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.1822C>T	p.Arg608Trp	missense_variant	Exon 16 of 25			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723748

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Pathogenic:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1157 of the SMARCA4 protein (p.Arg1157Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1157 amino acid residue in SMARCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22426308; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;D;D;.;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

4.1

H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.0

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.

Polyphen

1.0

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.

Vest4

0.97

MutPred

0.77

Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);Loss of methylation at R1157 (P = 0.0112);.;Loss of methylation at R1157 (P = 0.0112);.;.;.;

MVP

0.89

MPC

2.8

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.96

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over