rs201600949

Variant summary

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

The ENST00000344626.10(SMARCA4):​c.719C>A​(p.Pro240Gln) 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. 14/21 in silico tools predict a benign outcome for this variant. 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. P240L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SMARCA4
ENST00000344626.10 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32
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]

Genome browser will be placed here

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=0.118052185).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.719C>A p.Pro240Gln missense_variant 4/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.719C>A p.Pro240Gln missense_variant 4/35 ENST00000344626.10 NP_003063.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkuse as main transcriptc.719C>A p.Pro240Gln missense_variant 4/36 NM_001387283.1 ENSP00000495368
SMARCA4ENST00000344626.10 linkuse as main transcriptc.719C>A p.Pro240Gln missense_variant 4/351 NM_003072.5 ENSP00000343896 P4P51532-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1386750
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
684462
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:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The p.P240Q variant (also known as c.719C>A), located in coding exon 3 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 719. The proline at codon 240 is replaced by glutamine, an amino acid with similar properties. 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
Benign
0.079
BayesDel_addAF
Benign
-0.027
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Benign
0.58
DEOGEN2
Benign
0.20
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.51
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.92
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
-0.14
N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
MutationTaster
Benign
0.52
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
0.72
N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL
Benign
0.26
Sift
Benign
0.23
T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G
Benign
0.22
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen
0.57
P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P
Vest4
0.38
MutPred
0.26
Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);
MVP
0.60
MPC
0.24
ClinPred
0.31
T
GERP RS
3.4
Varity_R
0.039
gMVP
0.11

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: rs201600949; hg19: chr19-11097228; API