chr7-128392394-A-G

Variant names:

• chr7-128392394-A-G
• rs11549800
• NM_000883.4:c.*613T>C

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.*613T>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 0.00116 in 154,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.578
• 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

ENSG00000294385 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00116 (177/152352) while in subpopulation AMR AF = 0.00314 (48/15306). AF 95% confidence interval is 0.00243. There are 1 homozygotes in GnomAd4. There are 77 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 177 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.*613T>C		3_prime_UTR	Exon 17 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.*613T>C		3_prime_UTR	Exon 16 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.*613T>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.*613T>C		3_prime_UTR	Exon 17 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.*613T>C		3_prime_UTR	Exon 15 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.*613T>C		3_prime_UTR	Exon 15 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

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: 0.00165

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00132 AC: 3 AN: 2280 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1278

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00159 AC: 2 AN: 1258

Other (OTH) AF: 0.0102 AC: 1 AN: 98

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74506

African (AFR) AF: 0.000361 AC: 15 AN: 41588

American (AMR) AF: 0.00314 AC: 48 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00117

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis 11 (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.67
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11549800; hg19: chr7-128032448;