rs34724843

Positions:

• chr7-128400835-G-C
• chr7-128400835-G-A
• chr7-128400835-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000883.4(IMPDH1):​c.561C>G​(p.Asn187Lys) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IMPDH1 NM_000883.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.211

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain CBS 2 (size 58) in uniprot entity IMDH1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000883.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28854826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.561C>G	p.Asn187Lys	missense_variant	7/17	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11	c.561C>G	p.Asn187Lys	missense_variant	7/17	2	NM_000883.4	ENSP00000345096

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2023

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. 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. This variant has not been reported in the literature in individuals affected with IMPDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 187 of the IMPDH1 protein (p.Asn187Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Uncertain	0.43	.;.;.;T;.;T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.82	T;T;T;T;T;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.72	.;.;.;.;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D;D;.;D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.35	T;T;T;.;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T
Polyphen		0.040	.;.;.;.;B;.;.;.
Vest4		0.64
MutPred		0.42		.;.;.;.;.;.;.;Loss of helix (P = 0.0167);
MVP		0.65
MPC		0.69
ClinPred		0.81	D
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1042250; hg19: chr7-128040889; COSMIC: COSV58316999; COSMIC: COSV58316999;