7-128392779-C-T

Variant names:

• chr7-128392779-C-T
• rs72624976
• NM_000883.4:c.*228G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.38
• Publications: 7 publications found

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]

IMPDH1 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 11

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 10

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 358867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3584 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH1	NM_000883.4	MANE Select	c.*228G>A		3_prime_UTR	Exon 17 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.*228G>A		3_prime_UTR	Exon 16 of 16	NP_001096075.1
	IMPDH1	NM_001142576.2		c.*228G>A		3_prime_UTR	Exon 16 of 16	NP_001136048.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.*228G>A		3_prime_UTR	Exon 17 of 17	ENSP00000345096.6
	IMPDH1	ENST00000348127.11	TSL:1	c.*228G>A		3_prime_UTR	Exon 15 of 15	ENSP00000265385.8
	IMPDH1	ENST00000469328.5	TSL:5	n.*1222G>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000420756.1

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

African (AFR) AF: 0.00700 AC: 78 AN: 11148

American (AMR) AF: 0.0205 AC: 349 AN: 16992

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 279 AN: 12352

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28078

South Asian (SAS) AF: 0.00263 AC: 109 AN: 41442

European-Finnish (FIN) AF: 0.0112 AC: 294 AN: 26216

Middle Eastern (MID) AF: 0.0257 AC: 46 AN: 1788

European-Non Finnish (NFE) AF: 0.0378 AC: 9121 AN: 241588

Other (OTH) AF: 0.0279 AC: 648 AN: 23230

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

African (AFR) AF: 0.00718 AC: 298 AN: 41506

American (AMR) AF: 0.0215 AC: 329 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10606

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2544 AN: 67938

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 11 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Retinitis pigmentosa Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72624976; hg19: chr7-128032833;