7-128394575-C-T

Position:

• chr7-128394575-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000883.4(IMPDH1):​c.1575G>A​(p.Ala525=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,136 control chromosomes in the GnomAD database, including 57,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5025 hom., cov: 31)
  • Exomes 𝑓: 0.27 (52174 hom.)
• Consequence: IMPDH1 NM_000883.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.88

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 -16 ACMG points.

• BP6: Variant 7-128394575-C-T is Benign according to our data. Variant chr7-128394575-C-T is described in ClinVar as [Benign]. Clinvar id is 358873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.1575G>A	p.Ala525=	synonymous_variant	15/17	ENST00000338791.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.1575G>A	p.Ala525=	synonymous_variant	15/17	2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38542 AN: 151806 Hom.: 5018 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.252

GnomAD3 exomes AF: 0.272 AC: 68180 AN: 251108 Hom.: 9431 AF XY: 0.270 AC XY: 36635 AN XY: 135726

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.246

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.265 AC: 387809 AN: 1461210 Hom.: 52174 Cov.: 38 AF XY: 0.265 AC XY: 192704 AN XY: 726924

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.254 AC: 38575 AN: 151926 Hom.: 5025 Cov.: 31 AF XY: 0.258 AC XY: 19123 AN XY: 74236

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.359

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.255

Alfa AF: 0.238 Hom.: 2585

Bravo AF: 0.248

Asia WGS AF: 0.303 AC: 1057 AN: 3478

EpiCase AF: 0.252

EpiControl AF: 0.250

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

Leber congenital amaurosis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.73
CADD	Benign	5.5
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2228075; hg19: chr7-128034629; COSMIC: COSV58316076; COSMIC: COSV58316076;