rs146747026

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4_ModerateBS2

The NM_003072.5(SMARCA4):​c.4302C>A​(p.Asp1434Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000034 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

1
3
15

Clinical Significance

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

Conservation

PhyloP100: -1.66
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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=0.091701716).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.4398C>A p.Asp1466Glu missense_variant 31/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.4302C>A p.Asp1434Glu missense_variant 30/35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkuse as main transcriptc.4398C>A p.Asp1466Glu missense_variant 31/36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkuse as main transcriptc.4302C>A p.Asp1434Glu missense_variant 30/351 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkuse as main transcriptc.4308C>A p.Asp1436Glu missense_variant 30/35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkuse as main transcriptc.4212C>A p.Asp1404Glu missense_variant 30/355 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkuse as main transcriptc.4212C>A p.Asp1404Glu missense_variant 29/34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkuse as main transcriptc.4212C>A p.Asp1404Glu missense_variant 29/34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkuse as main transcriptc.4212C>A p.Asp1404Glu missense_variant 30/355 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkuse as main transcriptc.3723C>A p.Asp1241Glu missense_variant 27/32 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkuse as main transcriptc.2955C>A p.Asp985Glu missense_variant 23/28 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000644065.1 linkuse as main transcriptc.2937C>A p.Asp979Glu missense_variant 22/27 ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000642350.1 linkuse as main transcriptc.2796C>A p.Asp932Glu missense_variant 22/27 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkuse as main transcriptc.2664C>A p.Asp888Glu missense_variant 21/25 ENSP00000494159.1 A0A2R8Y526
SMARCA4ENST00000538456.4 linkuse as main transcriptc.468C>A p.Asp156Glu missense_variant 4/83 ENSP00000495197.1 A0A2R8YFK5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460276
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726504
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2022In 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. 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 not expected to disrupt SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 940887). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1466 of the SMARCA4 protein (p.Asp1466Glu). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 22, 2024This 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
Benign
0.15
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
6.8
DANN
Benign
0.94
DEOGEN2
Benign
0.27
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.36
N
LIST_S2
Uncertain
0.89
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Benign
0.092
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
-0.39
N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.93
N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.32
Sift
Benign
0.43
T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.53
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen
0.018
B;.;D;.;.;.;.;.;.;.;B;.;.;.;.;.;.;D;.;.;.;.;.
Vest4
0.25
MutPred
0.17
.;.;Loss of helix (P = 0.0068);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.0068);.;.;.;.;.;
MVP
0.67
MPC
1.0
ClinPred
0.55
D
GERP RS
-3.7
Varity_R
0.051
gMVP
0.67

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.

Other links and lift over

dbSNP: rs146747026; hg19: chr19-11152114; API