chr19-10984158-A-G

Variant summary

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

The NM_001387283.1(SMARCA4):​c.7A>G​(p.Thr3Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32
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]

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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=0.20992932).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.7A>G p.Thr3Ala missense_variant 2/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.7A>G p.Thr3Ala missense_variant 2/35 ENST00000344626.10 NP_003063.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkuse as main transcriptc.7A>G p.Thr3Ala missense_variant 2/36 NM_001387283.1 ENSP00000495368
SMARCA4ENST00000344626.10 linkuse as main transcriptc.7A>G p.Thr3Ala missense_variant 2/351 NM_003072.5 ENSP00000343896 P4P51532-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 07, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3 of the SMARCA4 protein (p.Thr3Ala). 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 not expected to disrupt SMARCA4 protein function. 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
0.26
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.017
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.80
.;T;.;.;.;.;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
1.0
L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
MutationTaster
Benign
0.98
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.3
N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL
Benign
0.25
Sift
Uncertain
0.021
D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G
Benign
0.083
T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen
0.0020
B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4
0.27
MutPred
0.17
Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);Loss of phosphorylation at T3 (P = 0.0012);
MVP
0.76
MPC
0.25
ClinPred
0.72
D
GERP RS
3.9
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.13
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

hg19: chr19-11094834; API