chr15-75372161-C-T

Variant summary

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

The NM_001145358.2(SIN3A):​c.3640G>A​(p.Val1214Ile) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SIN3A
NM_001145358.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93
Variant links:
Genes affected
SIN3A (HGNC:19353): (SIN3 transcription regulator family member A) The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, which are important for protein-protein interactions and may mediate repression by the Mad-Max complex. [provided by RefSeq, Jul 2008]

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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), SIN3A. . Gene score misZ 4.3926 (greater than the threshold 3.09). Trascript score misZ 5.1543 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 15q24 deletion syndrome, SIN3A-related intellectual disability syndrome due to a point mutation, congenital diaphragmatic hernia, SIN3A-related intellectual disability syndrome, autism, susceptibility to, 15.
BP4
Computational evidence support a benign effect (MetaRNN=0.18123975).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIN3ANM_001145358.2 linkuse as main transcriptc.3640G>A p.Val1214Ile missense_variant 21/21 ENST00000394947.8 NP_001138830.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SIN3AENST00000394947.8 linkuse as main transcriptc.3640G>A p.Val1214Ile missense_variant 21/211 NM_001145358.2 ENSP00000378402 P4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

SIN3A-related intellectual disability syndrome due to a point mutation Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBreda Genetics srlJan 12, 2021Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
21
DANN
Benign
0.89
DEOGEN2
Benign
0.29
T;T;T
Eigen
Benign
-0.075
Eigen_PC
Benign
0.090
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.93
.;.;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
L;L;L
MutationTaster
Benign
0.88
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.20
N;N;N
REVEL
Benign
0.052
Sift
Benign
0.39
T;T;T
Sift4G
Benign
0.41
T;T;T
Polyphen
0.073
B;B;B
Vest4
0.24
MutPred
0.38
Gain of ubiquitination at K1219 (P = 0.1235);Gain of ubiquitination at K1219 (P = 0.1235);Gain of ubiquitination at K1219 (P = 0.1235);
MVP
0.35
MPC
0.53
ClinPred
0.31
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.054
gMVP
0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75664502; API