7-128405923-C-G

Variant names:

• chr7-128405923-C-G
• rs72624946
• NM_000883.4:c.255-58G>C

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.255-58G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,453,036 control chromosomes in the GnomAD database, including 1 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 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000766 (115/150176) while in subpopulation AFR AF = 0.00262 (108/41300). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.255-58G>C		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.255-58G>C		intron_variant	Intron 3 of 16	2	NM_000883.4	ENSP00000345096.6

Frequencies

GnomAD3 genomes AF: 0.000766 AC: 115 AN: 150068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.000486

GnomAD4 exome AF: 0.0000683 AC: 89 AN: 1302860 Hom.: 1 Cov.: 29 AF XY: 0.0000622 AC XY: 40 AN XY: 642572

African (AFR) AF: 0.00250 AC: 64 AN: 25646

American (AMR) AF: 0.000252 AC: 7 AN: 27806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22016

East Asian (EAS) AF: 0.00 AC: 0 AN: 26144

South Asian (SAS) AF: 0.00 AC: 0 AN: 73918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3734

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1031734

Other (OTH) AF: 0.000303 AC: 16 AN: 52738

GnomAD4 genome AF: 0.000766 AC: 115 AN: 150176 Hom.: 0 Cov.: 32 AF XY: 0.000791 AC XY: 58 AN XY: 73366

African (AFR) AF: 0.00262 AC: 108 AN: 41300

American (AMR) AF: 0.000265 AC: 4 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67258

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000982

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		0.97
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs72624946; hg19: chr7-128045977;