7-128400645-C-T

Variant names:

• chr7-128400645-C-T
• rs2278294
• NM_000883.4:c.580-106G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000883.4(IMPDH1):​c.580-106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,265,432 control chromosomes in the GnomAD database, including 84,562 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 0.38 (10997 hom., cov: 33)
  • Exomes 𝑓: 0.36 (73565 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• Publications: 38 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4	c.580-106G>A		intron_variant	Intron 7 of 16	ENST00000338791.11	NP_000874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11	c.580-106G>A		intron_variant	Intron 7 of 16	2	NM_000883.4	ENSP00000345096.6

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57376 AN: 151962 Hom.: 10997 Cov.: 33

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.360 AC: 400663 AN: 1113352 Hom.: 73565 Cov.: 15 AF XY: 0.362 AC XY: 205092 AN XY: 566678

African (AFR) AF: 0.402 AC: 10672 AN: 26542

American (AMR) AF: 0.407 AC: 16080 AN: 39536

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 10134 AN: 23672

East Asian (EAS) AF: 0.500 AC: 18556 AN: 37118

South Asian (SAS) AF: 0.416 AC: 32329 AN: 77708

European-Finnish (FIN) AF: 0.379 AC: 19699 AN: 51918

Middle Eastern (MID) AF: 0.330 AC: 1375 AN: 4162

European-Non Finnish (NFE) AF: 0.341 AC: 273907 AN: 804054

Other (OTH) AF: 0.368 AC: 17911 AN: 48642

GnomAD4 genome AF: 0.378 AC: 57415 AN: 152080 Hom.: 10997 Cov.: 33 AF XY: 0.381 AC XY: 28312 AN XY: 74330

African (AFR) AF: 0.406 AC: 16840 AN: 41498

American (AMR) AF: 0.380 AC: 5807 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1499 AN: 3468

East Asian (EAS) AF: 0.545 AC: 2813 AN: 5164

South Asian (SAS) AF: 0.428 AC: 2063 AN: 4816

European-Finnish (FIN) AF: 0.374 AC: 3960 AN: 10584

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23338 AN: 67952

Other (OTH) AF: 0.368 AC: 776 AN: 2110

Alfa AF: 0.358 Hom.: 28537

Bravo AF: 0.380

Asia WGS AF: 0.474 AC: 1651 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2278294; hg19: chr7-128040699; COSMIC: COSV58316281; COSMIC: COSV58316281;