NM_000883.4:c.255-36C>A

Variant names:

• chr7-128405901-G-T
• rs72624947
• NM_000883.4:c.255-36C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000883.4(IMPDH1):​c.255-36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,480,188 control chromosomes in the GnomAD database, including 3 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 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000147 (22/149672) while in subpopulation EAS AF = 0.0041 (21/5118). AF 95% confidence interval is 0.00275. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.255-36C>A		intron_variant	Intron 3 of 16	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11	c.255-36C>A		intron_variant	Intron 3 of 16	2	NM_000883.4	ENSP00000345096.6

Frequencies

GnomAD3 genomes AF: 0.000147 AC: 22 AN: 149566 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 16 AN: 87228 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 309 AN: 1330516 Hom.: 3 Cov.: 31 AF XY: 0.000220 AC XY: 144 AN XY: 655912

African (AFR) AF: 0.00 AC: 0 AN: 26602

American (AMR) AF: 0.00 AC: 0 AN: 29298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23060

East Asian (EAS) AF: 0.0104 AC: 299 AN: 28696

South Asian (SAS) AF: 0.0000270 AC: 2 AN: 74110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3878

European-Non Finnish (NFE) AF: 9.52e-7 AC: 1 AN: 1050060

Other (OTH) AF: 0.000128 AC: 7 AN: 54714

GnomAD4 genome AF: 0.000147 AC: 22 AN: 149672 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 12 AN XY: 72940

African (AFR) AF: 0.00 AC: 0 AN: 41310

American (AMR) AF: 0.0000662 AC: 1 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00410 AC: 21 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66416

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		-0.16
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72624947; hg19: chr7-128045955;