dbSNP rs1057518949: IMPDH1:p.Thr310Pro (chr7-128398560-T-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_000883.4(IMPDH1):c.928A>C(p.Thr310Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T310T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

IMPDH1
NM_000883.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.99

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Leber congenital amaurosis 11
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa 10
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IMPDH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000883.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 7-128398560-T-G is Pathogenic according to our data. Variant chr7-128398560-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374177.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4 link	c.928A>C	p.Thr310Pro	missense_variant	Exon 10 of 17	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11 link	c.928A>C	p.Thr310Pro	missense_variant	Exon 10 of 17	2	NM_000883.4	ENSP00000345096.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leber congenital amaurosis 11

Pathogenic:1

Aug 22, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP4. -

Retinitis pigmentosa

Pathogenic:1

Dec 10, 2013

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;.;.;.;D;.;D;.;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;.;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

PhyloP100

8.0

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.4

D;D;D;D;.;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

D;D;D;D;.;D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D;D;D;D;D;D

Polyphen

0.99, 0.99

.;.;D;.;.;D;.;.;.

Vest4

0.61

MutPred

0.63

.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0429);

MVP

0.96

MPC

1.7

ClinPred

1.0

GERP RS

5.3

gMVP

0.92

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over