7-128396989-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000883.4(IMPDH1):c.1108G>A(p.Ala370Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,850 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 7 hom. )

Consequence

IMPDH1
NM_000883.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.53

Variant links:

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]

IMPDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013129264).

BP6

Variant 7-128396989-C-T is Benign according to our data. Variant chr7-128396989-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193819.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr7-128396989-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00189 (287/152232) while in subpopulation NFE AF= 0.00331 (225/68008). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4 link	c.1108G>A	p.Ala370Thr	missense_variant	Exon 11 of 17	ENST00000338791.11	NP_000874.2	P20839-6B3KRZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11 link	c.1108G>A	p.Ala370Thr	missense_variant	Exon 11 of 17	2	NM_000883.4	ENSP00000345096.6		P20839-6

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00190

AC:

479

AN:

251448

Hom.:

AF XY:

0.00190

AC XY:

258

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00334

AC:

4879

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

2433

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.00408

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00189

AC:

287

AN:

152232

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00331

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00272

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00222

AC:

270

EpiCase

AF:

0.00294

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leber congenital amaurosis 11;C1867299:Retinitis pigmentosa 10

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 08, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IMPDH1-related disorder

Benign:1

Aug 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Leber congenital amaurosis 11

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;.;.;T;.;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.098

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.72

T;T;T;T;T;T;.;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.57

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.61

N;N;N;N;.;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.20

T;T;T;T;.;T;T;T

Sift4G

Uncertain

0.044

D;T;T;T;T;T;T;T

Polyphen

0.0010, 0.043

.;.;B;.;.;B;.;.

Vest4

0.43

MVP

0.70

MPC

0.53

ClinPred

0.013

GERP RS

5.2

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over