rs878854243

Variant summary

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

The NM_003072.5(SMARCA4):ā€‹c.866T>Cā€‹(p.Met289Thr) 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 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

1
5
13

Clinical Significance

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

Conservation

PhyloP100: 3.23
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=0.18062517).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/35 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.866T>C p.Met289Thr missense_variant 6/36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/351 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 7/355 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 6/34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkuse as main transcriptc.866T>C p.Met289Thr missense_variant 7/355 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkuse as main transcriptc.278T>C p.Met93Thr missense_variant 3/32 ENSP00000496004.1 A0A2R8YGG3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460796
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
726716
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
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
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2022This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. 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: 238525). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 289 of the SMARCA4 protein (p.Met289Thr). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2022The p.M289T variant (also known as c.866T>C), located in coding exon 5 of the SMARCA4 gene, results from a T to C substitution at nucleotide position 866. The methionine at codon 289 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Benign
0.22
DEOGEN2
Benign
0.33
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.45
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.75
.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.18
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
1.4
L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.92
N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL
Uncertain
0.49
Sift
Benign
0.38
T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G
Benign
0.72
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen
0.44
B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4
0.43
MutPred
0.23
Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP
0.91
MPC
0.30
ClinPred
0.25
T
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.17
gMVP
0.043

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: rs878854243; hg19: chr19-11098348; API