chr19-11041512-C-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.4376C>T​(p.Thr1459Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1459S) has been classified as Uncertain significance.

Frequency

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

Consequence

SMARCA4
NM_003072.5 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.86
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 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.4472C>T p.Thr1491Ile missense_variant Exon 31 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.4376C>T p.Thr1459Ile missense_variant Exon 30 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.4472C>T p.Thr1491Ile missense_variant Exon 31 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.4376C>T p.Thr1459Ile missense_variant Exon 30 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.4382C>T p.Thr1461Ile missense_variant Exon 30 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.4286C>T p.Thr1429Ile missense_variant Exon 30 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.4286C>T p.Thr1429Ile missense_variant Exon 29 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.4286C>T p.Thr1429Ile missense_variant Exon 29 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.4286C>T p.Thr1429Ile missense_variant Exon 30 of 35 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.3797C>T p.Thr1266Ile missense_variant Exon 27 of 32 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkc.3029C>T p.Thr1010Ile missense_variant Exon 23 of 28 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000644065.1 linkc.3011C>T p.Thr1004Ile missense_variant Exon 22 of 27 ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000642350.1 linkc.2870C>T p.Thr957Ile missense_variant Exon 22 of 27 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkc.2738C>T p.Thr913Ile missense_variant Exon 21 of 25 ENSP00000494159.1 A0A2R8Y526
SMARCA4ENST00000538456.4 linkc.542C>T p.Thr181Ile missense_variant Exon 4 of 8 3 ENSP00000495197.1 A0A2R8YFK5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461656
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727142
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Oct 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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: 537775). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1491 of the SMARCA4 protein (p.Thr1491Ile). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
Mar 18, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.T1491I variant (also known as c.4472C>T), located in coding exon 30 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4472. The threonine at codon 1491 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.43
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
-0.84
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-2.8
D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.092
T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.12
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen
0.84
P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4
0.76
MutPred
0.19
.;.;Loss of phosphorylation at T1491 (P = 0.0318);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of phosphorylation at T1491 (P = 0.0318);.;.;.;.;.;
MVP
0.52
MPC
2.2
ClinPred
0.96
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.71
gMVP
0.87

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: rs1555788341; hg19: chr19-11152188; API