7-128396955-T-A

Variant names:

• chr7-128396955-T-A
• rs61751223
• NM_000883.4:c.1142A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000883.4(IMPDH1):​c.1142A>T​(p.His381Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H381R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IMPDH1 NM_000883.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41567454).

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.1142A>T	p.His381Leu	missense	Exon 11 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.1112A>T	p.His371Leu	missense	Exon 10 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.1043A>T	p.His348Leu	missense	Exon 10 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.1142A>T	p.His381Leu	missense	Exon 11 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.1034A>T	p.His345Leu	missense	Exon 9 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.1034A>T	p.His345Leu	missense	Exon 9 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461140 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111684

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.43	T
PhyloP100		6.1
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.51
Sift	Benign	0.073	T
Sift4G	Benign	0.077	T
Polyphen		0.016	B
Vest4		0.45
MVP		0.79
MPC		0.67
ClinPred		0.96	D
GERP RS		3.9
gMVP		0.65
Mutation Taster		=81/19	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: rs61751223; hg19: chr7-128037009;