rs72624968

Variant names:

• chr7-128394423-G-A
• rs72624968
• NM_000883.4:c.1694+33C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000883.4(IMPDH1):​c.1694+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,944 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0099 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (155 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00987 (1502/152236) while in subpopulation NFE AF = 0.0149 (1016/68012). AF 95% confidence interval is 0.0142. There are 15 homozygotes in GnomAd4. There are 692 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1502 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.1694+33C>T		intron_variant	Intron 15 of 16	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11	c.1694+33C>T		intron_variant	Intron 15 of 16	2	NM_000883.4	ENSP00000345096.6

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1502 AN: 152118 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0103 AC: 2590 AN: 251294 AF XY: 0.0102

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0137 AC: 19962 AN: 1461708 Hom.: 155 Cov.: 34 AF XY: 0.0133 AC XY: 9660 AN XY: 727158

African (AFR) AF: 0.00248 AC: 83 AN: 33476

American (AMR) AF: 0.0117 AC: 524 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 434 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00291 AC: 251 AN: 86250

European-Finnish (FIN) AF: 0.00534 AC: 285 AN: 53330

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17627 AN: 1111934

Other (OTH) AF: 0.0118 AC: 711 AN: 60390

GnomAD4 genome AF: 0.00987 AC: 1502 AN: 152236 Hom.: 15 Cov.: 32 AF XY: 0.00930 AC XY: 692 AN XY: 74418

African (AFR) AF: 0.00349 AC: 145 AN: 41538

American (AMR) AF: 0.0130 AC: 199 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1016 AN: 68012

Other (OTH) AF: 0.0109 AC: 23 AN: 2108

Alfa AF: 0.0138 Hom.: 6

Bravo AF: 0.0103

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.2
DANN	Benign	0.79
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs72624968; hg19: chr7-128034477;