rs61751223

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-128396955-T-C
• chr7-128396955-T-A
• chr7-128396955-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000883.4(IMPDH1):​c.1142A>G​(p.His381Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00334 in 1,613,000 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H381Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (14 hom.)
• Consequence: IMPDH1 NM_000883.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 6.05
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01203832).
• BP6: Variant 7-128396955-T-C is Benign according to our data. Variant chr7-128396955-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 707014.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00212 (322/151904) while in subpopulation NFE AF = 0.0035 (238/67932). AF 95% confidence interval is 0.00314. There are 0 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 322 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.1142A>G	p.His381Arg	missense	Exon 11 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.1112A>G	p.His371Arg	missense	Exon 10 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.1043A>G	p.His348Arg	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>G	p.His381Arg	missense	Exon 11 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.1034A>G	p.His345Arg	missense	Exon 9 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.1034A>G	p.His345Arg	missense	Exon 9 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 151788 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00216 AC: 542 AN: 251250 AF XY: 0.00236

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00347 AC: 5065 AN: 1461096 Hom.: 14 Cov.: 31 AF XY: 0.00337 AC XY: 2452 AN XY: 726908

African (AFR) AF: 0.000598 AC: 20 AN: 33458

American (AMR) AF: 0.00114 AC: 51 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

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

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86230

European-Finnish (FIN) AF: 0.000787 AC: 42 AN: 53348

Middle Eastern (MID) AF: 0.00362 AC: 20 AN: 5528

European-Non Finnish (NFE) AF: 0.00415 AC: 4618 AN: 1111642

Other (OTH) AF: 0.00333 AC: 201 AN: 60344

GnomAD4 genome AF: 0.00212 AC: 322 AN: 151904 Hom.: 0 Cov.: 32 AF XY: 0.00217 AC XY: 161 AN XY: 74246

African (AFR) AF: 0.000700 AC: 29 AN: 41420

American (AMR) AF: 0.00301 AC: 46 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 67932

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00230 Hom.: 0

Bravo AF: 0.00228

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00228 AC: 277

EpiCase AF: 0.00414

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Leber congenital amaurosis 11 (1)
-	-	1	Retinal dystrophy (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.87	T
PhyloP100		6.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.27
Sift	Benign	0.18	T
Sift4G	Benign	0.094	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.79
MPC		0.65
ClinPred		0.028	T
GERP RS		3.9
gMVP		0.55
Mutation Taster		=88/12	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;