chr7-128392410-C-T

Position:

• chr7-128392410-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000883.4(IMPDH1):​c.*597G>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 0.0177 in 155,022 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 33)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -7.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-128392410-C-T is Benign according to our data. Variant chr7-128392410-C-T is described in ClinVar as [Benign]. Clinvar id is 358860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0177 (2700/152336) while in subpopulation SAS AF= 0.0549 (265/4828). AF 95% confidence interval is 0.0495. There are 40 homozygotes in gnomad4. There are 1324 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2700 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.*597G>A		3_prime_UTR_variant	17/17	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11	c.*597G>A		3_prime_UTR_variant	17/17	2	NM_000883.4	ENSP00000345096

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2702 AN: 152218 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0156 AC: 42 AN: 2686 Hom.: 0 Cov.: 0 AF XY: 0.0175 AC XY: 26 AN XY: 1488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0617

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.00862

GnomAD4 genome AF: 0.0177 AC: 2700 AN: 152336 Hom.: 40 Cov.: 33 AF XY: 0.0178 AC XY: 1324 AN XY: 74502

Gnomad4 AFR AF: 0.00611

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0549

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0185 Hom.: 5

Bravo AF: 0.0170

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.91
CADD	Benign	0.011
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1803821; hg19: chr7-128032464;