19-10986367-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_003072.5(SMARCA4):​c.534C>G​(p.His178Gln) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_003072.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0200
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.30898267).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.534C>G p.His178Gln missense_variant Exon 4 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.534C>G p.His178Gln missense_variant Exon 4 of 35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.534C>G p.His178Gln missense_variant Exon 4 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.534C>G p.His178Gln missense_variant Exon 4 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.534C>G p.His178Gln missense_variant Exon 4 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.534C>G p.His178Gln missense_variant Exon 5 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.534C>G p.His178Gln missense_variant Exon 4 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.534C>G p.His178Gln missense_variant Exon 4 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.534C>G p.His178Gln missense_variant Exon 5 of 35 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.-55C>G upstream_gene_variant ENSP00000496004.1 A0A2R8YGG3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1
Jul 15, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Jul 19, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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: 470437). 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 histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 178 of the SMARCA4 protein (p.His178Gln). -

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 05, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.H178Q variant (also known as c.534C>G), located in coding exon 3 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 534. The histidine at codon 178 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Benign
-0.10
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.65
D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.93
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
-0.29
N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.1
N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.18
T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G
Benign
0.61
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen
0.0090
B;.;D;.;.;.;.;.;.;.;B;.;.;.;.;.;.;D
Vest4
0.33
MutPred
0.52
Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);Loss of catalytic residue at L180 (P = 0.0602);
MVP
0.76
MPC
0.89
ClinPred
0.71
D
GERP RS
-1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.14
gMVP
0.54

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: rs759429379; hg19: chr19-11097043; API