rs2288550

chr7-128398501-C-Gchr7-128398501-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000883.4(IMPDH1):c.987G>C(p.Leu329=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,462 control chromosomes in the GnomAD database, including 23,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L329L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1650 hom., cov: 31)
  • Exomes 𝑓: 0.17 (22090 hom.)
• Consequence: IMPDH1 NM_000883.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.20

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-128398501-C-G is Benign according to our data. Variant chr7-128398501-C-G is described in ClinVar as [Benign]. Clinvar id is 358876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128398501-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.987G>C	p.Leu329=	synonymous_variant	10/17	ENST00000338791.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.987G>C	p.Leu329=	synonymous_variant	10/17	2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21605 AN: 152056 Hom.: 1647 Cov.: 31

Gnomad AFR AF: 0.0773

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.157 AC: 39491 AN: 250902 Hom.: 3373 AF XY: 0.165 AC XY: 22338 AN XY: 135668

Gnomad AFR exome AF: 0.0753

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.170 AC: 248985 AN: 1461288 Hom.: 22090 Cov.: 33 AF XY: 0.173 AC XY: 125537 AN XY: 726956

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.0895

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.142 AC: 21618 AN: 152174 Hom.: 1650 Cov.: 31 AF XY: 0.144 AC XY: 10715 AN XY: 74382

Gnomad4 AFR AF: 0.0772

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.156

Alfa AF: 0.163 Hom.: 619

Bravo AF: 0.129

Asia WGS AF: 0.178 AC: 617 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Leber congenital amaurosis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	6.6
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2288550; hg19: chr7-128038555; COSMIC: COSV58315354; COSMIC: COSV58315354;