19-10984233-C-A

Position:

chr19-10984233-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001387283.1(SMARCA4):c.82C>A(p.Leu28Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0220

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.07142362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.82C>A	p.Leu28Met	missense_variant	2/36	ENST00000646693.2
SMARCA4	NM_003072.5 linkuse as main transcript	c.82C>A	p.Leu28Met	missense_variant	2/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.82C>A	p.Leu28Met	missense_variant	2/36		NM_001387283.1
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.82C>A	p.Leu28Met	missense_variant	2/35	1	NM_003072.5	P4	P51532-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244686

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133736

show subpopulations

Gnomad AFR exome

AF:

0.0000665

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 537773). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs776688705, gnomAD 0.007%). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 28 of the SMARCA4 protein (p.Leu28Met). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.17

T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.84

.;T;.;.;.;.;T;.;.;.;D;D;.;T;T;T;T;T;D

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.071

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.69

N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.

MutationTaster

Benign

0.81

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

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.080

N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N

REVEL

Benign

0.26

Sift

Benign

0.086

T;.;.;.;.;.;.;.;.;.;T;.;.;T;.;T;.;T;T

Sift4G

Benign

0.46

T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T

Polyphen

0.0060

B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B

Vest4

0.28

MutPred

0.20

Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);

MVP

0.48

MPC

0.25

ClinPred

0.045

GERP RS

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.057

gMVP

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over