rs543042380

Variant names:

• chr7-128392784-G-A
• rs543042380
• NM_000883.4:c.*223C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-128392784-G-A
• chr7-128392784-G-C
• chr7-128392784-G-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.*223C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 561,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: IMPDH1 NM_000883.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.519
• 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=-0.86).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000657 (10/152228) while in subpopulation SAS AF = 0.00166 (8/4826). AF 95% confidence interval is 0.000824. There are 0 homozygotes in GnomAd4. There are 9 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 10 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.*223C>T		3_prime_UTR	Exon 17 of 17	NP_000874.2
	IMPDH1	NM_001102605.2		c.*223C>T		3_prime_UTR	Exon 16 of 16	NP_001096075.1	P20839-5
	IMPDH1	NM_001142576.2		c.*223C>T		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.*223C>T		3_prime_UTR	Exon 17 of 17	ENSP00000345096.6	P20839-6
	IMPDH1	ENST00000348127.11	TSL:1	c.*223C>T		3_prime_UTR	Exon 15 of 15	ENSP00000265385.8	P20839-3
	IMPDH1	ENST00000955327.1		c.*223C>T		3_prime_UTR	Exon 15 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 49 AN: 409240 Hom.: 0 Cov.: 4 AF XY: 0.000158 AC XY: 34 AN XY: 215396

African (AFR) AF: 0.00 AC: 0 AN: 11302

American (AMR) AF: 0.0000580 AC: 1 AN: 17244

Ashkenazi Jewish (ASJ) AF: 0.0000797 AC: 1 AN: 12540

East Asian (EAS) AF: 0.0000350 AC: 1 AN: 28574

South Asian (SAS) AF: 0.00103 AC: 43 AN: 41712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1824

European-Non Finnish (NFE) AF: 0.00000814 AC: 2 AN: 245558

Other (OTH) AF: 0.0000423 AC: 1 AN: 23634

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74432

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

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	-0.86
CADD	Benign	0.73
DANN	Benign	0.55
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs543042380; hg19: chr7-128032838;