19-10984159-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001387283.1(SMARCA4):​c.8C>T​(p.Thr3Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

2
14
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.8C>T p.Thr3Ile missense_variant 2/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.8C>T p.Thr3Ile 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.8C>T p.Thr3Ile missense_variant 2/36 NM_001387283.1 ENSP00000495368
SMARCA4ENST00000344626.10 linkuse as main transcriptc.8C>T p.Thr3Ile missense_variant 2/351 NM_003072.5 ENSP00000343896 P4P51532-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247758
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134544
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461432
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727036
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 17, 2023Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. ClinVar contains an entry for this variant (Variation ID: 1500930). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3 of the SMARCA4 protein (p.Thr3Ile). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2023The p.T3I variant (also known as c.8C>T), located in coding exon 1 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 8. The threonine at codon 3 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is 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). 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
Pathogenic
0.72
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.45
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
1.0
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
0.72
T
PROVEAN
Benign
-2.0
N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL
Uncertain
0.54
Sift
Uncertain
0.0020
D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G
Uncertain
0.024
D;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;D;D;D
Polyphen
0.61
P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P
Vest4
0.52
MutPred
0.24
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
0.74
MPC
0.27
ClinPred
0.64
D
GERP RS
5.0
Varity_R
0.34
gMVP
0.22

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: rs1339941779; hg19: chr19-11094835; API