7-128392779-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000883.4(IMPDH1):c.*228G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 554,958 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (77 hom., cov: 33)
  • Exomes 𝑓: 0.027 (216 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.38

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 7-128392779-C-T is Benign according to our data. Variant chr7-128392779-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 358867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0236 (3584/152124) while in subpopulation NFE AF= 0.0374 (2544/67938). AF 95% confidence interval is 0.0362. There are 77 homozygotes in gnomad4. There are 1633 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3586 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.*228G>A		3_prime_UTR_variant	17/17	ENST00000338791.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.*228G>A		3_prime_UTR_variant	17/17	2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3586 AN: 152006 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.00720

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0271 AC: 10925 AN: 402834 Hom.: 216 Cov.: 3 AF XY: 0.0258 AC XY: 5476 AN XY: 212004

Gnomad4 AFR exome AF: 0.00700

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.0000356

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0378

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0236 AC: 3584 AN: 152124 Hom.: 77 Cov.: 33 AF XY: 0.0220 AC XY: 1633 AN XY: 74388

Gnomad4 AFR AF: 0.00718

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.0258

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 11 Benign:1

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

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	-0.68
Cadd	Benign	5.2
Dann	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72624976; hg19: chr7-128032833;