rs72624951

Variant names:

• chr7-128403649-C-T
• rs72624951
• NM_000883.4:c.402+57G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000883.4(IMPDH1):​c.402+57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,498,466 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (21 hom.)
• Consequence: IMPDH1 NM_000883.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 10

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-128403649-C-T is Benign according to our data. Variant chr7-128403649-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1198217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00185 (282/152276) while in subpopulation SAS AF = 0.00767 (37/4822). AF 95% confidence interval is 0.00572. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 282 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.402+57G>A		intron	N/A	NP_000874.2
	IMPDH1	NM_001102605.2		c.372+57G>A		intron	N/A	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.303+57G>A		intron	N/A	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.402+57G>A		intron	N/A	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.294+57G>A		intron	N/A	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.294+57G>A		intron	N/A	ENSP00000625386.1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00296 AC: 3979 AN: 1346190 Hom.: 21 AF XY: 0.00315 AC XY: 2134 AN XY: 676538

African (AFR) AF: 0.000482 AC: 15 AN: 31128

American (AMR) AF: 0.000314 AC: 14 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39040

South Asian (SAS) AF: 0.00988 AC: 830 AN: 83978

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53318

Middle Eastern (MID) AF: 0.00325 AC: 18 AN: 5540

European-Non Finnish (NFE) AF: 0.00289 AC: 2910 AN: 1006662

Other (OTH) AF: 0.00239 AC: 135 AN: 56550

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74460

African (AFR) AF: 0.000674 AC: 28 AN: 41562

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4822

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IMPDH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.68
PhyloP100		1.0
PromoterAI		-0.025	Neutral
Mutation Taster		=3/97	disease causing

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: rs72624951; hg19: chr7-128043703;