rs121912551
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000883.4(IMPDH1):c.1057G>A(p.Val353Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
IMPDH1
NM_000883.4 missense
NM_000883.4 missense
Scores
5
12
Clinical Significance
Conservation
PhyloP100: 2.95
Genes affected
IMPDH1 (HGNC:6052): (inosine monophosphate dehydrogenase 1) The protein encoded by this gene acts as a homotetramer to regulate cell growth. The encoded protein is an enzyme that catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5'-monophosphate (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides. Defects in this gene are a cause of retinitis pigmentosa type 10 (RP10). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IMPDH1 | NM_000883.4 | c.1057G>A | p.Val353Ile | missense_variant | 10/17 | ENST00000338791.11 | NP_000874.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IMPDH1 | ENST00000338791.11 | c.1057G>A | p.Val353Ile | missense_variant | 10/17 | 2 | NM_000883.4 | ENSP00000345096 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000480 AC: 12AN: 249824Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135286
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GnomAD4 exome AF: 0.0000664 AC: 97AN: 1460992Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51AN XY: 726816
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Retinitis pigmentosa 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2002 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 10, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 353 of the IMPDH1 protein (p.Val353Ile). This variant is present in population databases (rs121912551, gnomAD 0.008%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 11875050). This variant is also known as V268I. ClinVar contains an entry for this variant (Variation ID: 14835). 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. Experimental studies have shown that this missense change affects IMPDH1 function (PMID: 15882147). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;.;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;.;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;.;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;D
Polyphen
0.61, 0.54
.;.;P;.;.;P;.;.;.
Vest4
MVP
MPC
0.48
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at