rs764152134

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6

The NM_003072.5(SMARCA4):​c.3799G>A​(p.Gly1267Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 779,766 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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=0.2387389).
BP6
Variant 19-11033791-G-A is Benign according to our data. Variant chr19-11033791-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.3799G>A p.Gly1267Ser missense_variant 27/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.3799G>A p.Gly1267Ser missense_variant 27/35 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.3799G>A p.Gly1267Ser missense_variant 27/36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkuse as main transcriptc.3799G>A p.Gly1267Ser missense_variant 27/351 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643995.1 linkuse as main transcriptc.3211G>A p.Gly1071Ser missense_variant 24/32 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkuse as main transcriptc.2443G>A p.Gly815Ser missense_variant 20/28 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000642350.1 linkuse as main transcriptc.2284G>A p.Gly762Ser missense_variant 19/27 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkuse as main transcriptc.2152G>A p.Gly718Ser missense_variant 18/25 ENSP00000494159.1 A0A2R8Y526
SMARCA4ENST00000643549.1 linkuse as main transcriptc.3774+274G>A intron_variant ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkuse as main transcriptc.3774+274G>A intron_variant 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkuse as main transcriptc.3774+274G>A intron_variant ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkuse as main transcriptc.3774+274G>A intron_variant ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkuse as main transcriptc.3774+274G>A intron_variant 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000644065.1 linkuse as main transcriptc.2499+274G>A intron_variant ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000538456.4 linkuse as main transcriptc.30+274G>A intron_variant 3 ENSP00000495197.1 A0A2R8YFK5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000408
AC:
1
AN:
245330
Hom.:
0
AF XY:
0.00000746
AC XY:
1
AN XY:
134082
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000159
AC:
1
AN:
627620
Hom.:
0
Cov.:
0
AF XY:
0.00000292
AC XY:
1
AN XY:
341942
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:
0.0000143
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
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 17, 2022This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1267 of the SMARCA4 protein (p.Gly1267Ser). This variant is present in population databases (rs764152134, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 480652). 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 tolerated. 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. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 14, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Uncertain
0.012
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;T;T;T;.;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.89
.;.;D;D;D;D
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.24
T;T;T;T;T;T
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
0.42
N;.;N;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.44
N;.;N;.;.;.
REVEL
Uncertain
0.34
Sift
Benign
0.11
T;.;T;.;.;.
Sift4G
Benign
0.47
T;.;T;T;.;.
Polyphen
1.0
D;D;D;D;.;.
Vest4
0.34
MutPred
0.22
Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);Loss of glycosylation at S1266 (P = 0.0239);.;.;
MVP
0.81
MPC
1.4
ClinPred
0.41
T
GERP RS
5.2
Varity_R
0.12
gMVP
0.66

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: rs764152134; hg19: chr19-11144467; API