Genetic Variant NM_000883.4:c.849T>A (chr7-128400120-A-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1PM2PP3PP5_Moderate

The NM_000883.4(IMPDH1):c.849T>A(p.Asn283Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N283S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

IMPDH1
NM_000883.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.578

Publications

0 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):

IMPDH1-related retinopathy
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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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 9 ACMG points.

PS1

Transcript NM_000883.4 (IMPDH1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

PP5

Variant 7-128400120-A-T is Pathogenic according to our data. Variant chr7-128400120-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1457411.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IMPDH1	NM_000883.4	MANE Select	c.849T>A	p.Asn283Lys	missense	Exon 9 of 17	NP_000874.2
IMPDH1	NM_001102605.2		c.819T>A	p.Asn273Lys	missense	Exon 8 of 16	NP_001096075.1	P20839-5
IMPDH1	NM_001142576.2		c.750T>A	p.Asn250Lys	missense	Exon 8 of 16	NP_001136048.1	P20839-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.849T>A	p.Asn283Lys	missense	Exon 9 of 17	ENSP00000345096.6	P20839-6
IMPDH1	ENST00000348127.11	TSL:1	c.741T>A	p.Asn247Lys	missense	Exon 7 of 15	ENSP00000265385.8	P20839-3
IMPDH1	ENST00000955327.1		c.741T>A	p.Asn247Lys	missense	Exon 7 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.47

PhyloP100

0.58

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.64

Sift

Uncertain

0.015

Sift4G

Benign

0.43

Polyphen

0.98

Vest4

0.82

MutPred

0.65

Gain of helix (P = 0.0325)

MVP

0.93

MPC

1.6

ClinPred

0.98

GERP RS

1.3

gMVP

0.91

Mutation Taster

=0/100

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over