rs1060502059

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The ENST00000344626.10(SMARCA4):c.220A>C(p.Lys74Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,582,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SMARCA4
ENST00000344626.10 missense, splice_region

Scores

Splicing: ADA: 0.6030

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 9.32

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 Likely_benign. Variant got -3 ACMG points.

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.

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.220A>C	p.Lys74Gln	missense_variant, splice_region_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.220A>C	p.Lys74Gln	missense_variant, splice_region_variant	2/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.220A>C	p.Lys74Gln	missense_variant, splice_region_variant	2/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.220A>C	p.Lys74Gln	missense_variant, splice_region_variant	2/35	1	NM_003072.5	ENSP00000343896	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000518

AC:

AN:

192948

Hom.:

AF XY:

0.00000960

AC XY:

AN XY:

104136

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000210

AC:

AN:

1430520

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

708860

show subpopulations

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:

0.0000237

Gnomad4 OTH exome

AF:

0.0000677

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.0000936

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 74 of the SMARCA4 protein (p.Lys74Gln). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408602). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2023	- -

Intellectual disability, autosomal dominant 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

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

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.53

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

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.1

L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.2

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

REVEL

Uncertain

0.61

Sift

Uncertain

0.0040

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

Sift4G

Benign

0.55

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

Polyphen

0.98

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

Vest4

0.66

MutPred

0.30

Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);Loss of methylation at K74 (P = 0.0019);

MVP

0.85

MPC

0.77

ClinPred

0.72

GERP RS

4.8

Varity_R

0.34

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.60

dbscSNV1_RF

Benign

0.62

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