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GeneBe

19-10985304-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001387283.1(SMARCA4):c.254C>T(p.Ser85Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S85S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.447
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 Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant where missense usually causes diseases, SMARCA4
BP4
Computational evidence support a benign effect (MetaRNN=0.09379864).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.254C>T p.Ser85Leu missense_variant 3/36 ENST00000646693.2
SMARCA4NM_003072.5 linkuse as main transcriptc.254C>T p.Ser85Leu missense_variant 3/35 ENST00000344626.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMARCA4ENST00000646693.2 linkuse as main transcriptc.254C>T p.Ser85Leu missense_variant 3/36 NM_001387283.1
SMARCA4ENST00000344626.10 linkuse as main transcriptc.254C>T p.Ser85Leu missense_variant 3/351 NM_003072.5 P4P51532-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251338
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135910
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461812
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 15, 2019The SMARCA4 c.254C>T; p.Ser85Leu variant (rs751542188), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 470310). This variant is found in the general population with a low overall allele frequency of 0.002% (5/282696 alleles) in the Genome Aggregation Database. The serine at codon 85 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. -
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 testingInvitaeJan 19, 2024This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 85 of the SMARCA4 protein (p.Ser85Leu). This variant is present in population databases (rs751542188, 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: 470310). 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 with a negative predictive value of 95%. 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. -
SMARCA4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 27, 2023The SMARCA4 c.254C>T variant is predicted to result in the amino acid substitution p.Ser85Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11095980-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/470310). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 31, 2022This 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
0.092
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.29
Cadd
Benign
22
Dann
Uncertain
0.99
DEOGEN2
Benign
0.37
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.25
N
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.094
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
0.55
N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.8
N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL
Benign
0.17
Sift
Benign
0.17
T;.;.;.;.;.;.;.;.;.;T;.;.;T;.;T;.;T;T
Sift4G
Benign
0.39
T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen
0.019
B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4
0.31
MutPred
0.24
Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);Gain of catalytic residue at S85 (P = 0.0111);
MVP
0.49
MPC
0.23
ClinPred
0.13
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.070
gMVP
0.10

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: rs751542188; hg19: chr19-11095980; COSMIC: COSV60798215; COSMIC: COSV60798215; API