rs72624951

chr7-128403649-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000883.4(IMPDH1):c.402+57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,498,466 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (21 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00185 (282/152276) while in subpopulation SAS AF= 0.00767 (37/4822). AF 95% confidence interval is 0.00572. There are 0 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.402+57G>A		intron_variant		ENST00000338791.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.402+57G>A		intron_variant		2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00296 AC: 3979 AN: 1346190 Hom.: 21 AF XY: 0.00315 AC XY: 2134 AN XY: 676538

Gnomad4 AFR exome AF: 0.000482

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00988

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74460

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2019

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 27032803, 20718729) -

IMPDH1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.68

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: rs72624951; hg19: chr7-128043703;