7-128392373-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000883.4(IMPDH1):c.*634C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0177 in 154,144 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 33)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 5.03

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]

LOC107986845 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 7-128392373-G-A is Benign according to our data. Variant chr7-128392373-G-A is described in ClinVar as [Benign]. Clinvar id is 358858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0178 (2707/152362) while in subpopulation SAS AF= 0.055 (266/4834). AF 95% confidence interval is 0.0496. There are 39 homozygotes in gnomad4. There are 1329 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2709 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPDH1	NM_000883.4	c.*634C>T		3_prime_UTR_variant	17/17	ENST00000338791.11
LOC107986845	NR_148338.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPDH1	ENST00000338791.11	c.*634C>T		3_prime_UTR_variant	17/17	2	NM_000883.4

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2709 AN: 152244 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0135 AC: 24 AN: 1782 Hom.: 0 Cov.: 0 AF XY: 0.0144 AC XY: 14 AN XY: 970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.0833

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0581

Gnomad4 FIN exome AF: 0.00214

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0178 AC: 2707 AN: 152362 Hom.: 39 Cov.: 33 AF XY: 0.0178 AC XY: 1329 AN XY: 74510

Gnomad4 AFR AF: 0.00613

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0194 Hom.: 5

Bravo AF: 0.0170

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

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	-0.34
Cadd	Benign	18
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1803822; hg19: chr7-128032427;