rs121912551

chr7-128398431-C-T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.1057G>A	p.Val353Ile	missense_variant	10/17	ENST00000338791.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.1057G>A	p.Val353Ile	missense_variant	10/17	2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000480 AC: 12 AN: 249824 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000799

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1460992 Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51 AN XY: 726816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000738

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

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

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	0.96	A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.70	N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.051	T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T;T;T;D
Polyphen		0.61, 0.54	.;.;P;.;.;P;.;.;.
Vest4		0.26
MVP		0.39
MPC		0.48
ClinPred		0.33	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.67

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

Other links and lift over

dbSNP: rs121912551; hg19: chr7-128038485; COSMIC: COSV58317863; COSMIC: COSV58317863;