rs72624973

Variant names:

• chr7-128392870-C-G
• rs72624973
• NM_000883.4:c.*137G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-128392870-C-G
• chr7-128392870-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000883.4(IMPDH1):​c.*137G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 837,850 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.24
• 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):

• IMPDH1-related retinopathy

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000289 (44/152234) while in subpopulation SAS AF = 0.00332 (16/4826). AF 95% confidence interval is 0.00208. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 44 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH1	NM_000883.4	MANE Select	c.*137G>C		3_prime_UTR	Exon 17 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.*137G>C		3_prime_UTR	Exon 16 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.*137G>C		3_prime_UTR	Exon 16 of 16	NP_001136048.1	P20839-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.*137G>C		3_prime_UTR	Exon 17 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.*137G>C		3_prime_UTR	Exon 15 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.*137G>C		3_prime_UTR	Exon 15 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152116 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000496 AC: 340 AN: 685616 Hom.: 2 Cov.: 9 AF XY: 0.000627 AC XY: 226 AN XY: 360484

African (AFR) AF: 0.00 AC: 0 AN: 18850

American (AMR) AF: 0.000166 AC: 6 AN: 36224

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 49 AN: 18304

East Asian (EAS) AF: 0.00 AC: 0 AN: 34160

South Asian (SAS) AF: 0.00266 AC: 165 AN: 61966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43586

Middle Eastern (MID) AF: 0.00343 AC: 9 AN: 2624

European-Non Finnish (NFE) AF: 0.000216 AC: 94 AN: 435712

Other (OTH) AF: 0.000497 AC: 17 AN: 34190

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152234 Hom.: 1 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74426

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000264

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis 11 (1)
-	1	-	not provided (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs72624973; hg19: chr7-128032924;