Genetic Variant IMPDH1:c.*597G>A (chr7-128392410-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000883.4(IMPDH1):c.*597G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 155,022 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 33)

Exomes 𝑓: 0.016 ( 0 hom. )

Consequence

IMPDH1
NM_000883.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -7.90

Publications

5 publications found

Variant links:

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

IMPDH1 links:

ENSG00000294385 (HGNC:):

ENSG00000294385 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 7-128392410-C-T is Benign according to our data. Variant chr7-128392410-C-T is described in ClinVar as Benign. ClinVar VariationId is 358860.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 = 0.0177 (2700/152336) while in subpopulation SAS AF = 0.0549 (265/4828). AF 95% confidence interval is 0.0495. There are 40 homozygotes in GnomAd4. There are 1324 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2700 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IMPDH1	NM_000883.4	MANE Select	c.*597G>A	3_prime_UTR	Exon 17 of 17	NP_000874.2
IMPDH1	NM_001102605.2		c.*597G>A	3_prime_UTR	Exon 16 of 16	NP_001096075.1	P20839-5
IMPDH1	NM_001142576.2		c.*597G>A	3_prime_UTR	Exon 16 of 16	NP_001136048.1	P20839-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.*597G>A	3_prime_UTR	Exon 17 of 17	ENSP00000345096.6	P20839-6
IMPDH1	ENST00000348127.11	TSL:1	c.*597G>A	3_prime_UTR	Exon 15 of 15	ENSP00000265385.8	P20839-3
IMPDH1	ENST00000955327.1		c.*597G>A	3_prime_UTR	Exon 15 of 15	ENSP00000625386.1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2702

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00613

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0206

GnomAD4 exome

AF:

0.0156

AC:

AN:

2686

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

AN XY:

1488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00602

AC:

AN:

332

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0617

AC:

AN:

162

European-Finnish (FIN)

AF:

0.00205

AC:

AN:

488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0170

AC:

AN:

1530

Other (OTH)

AF:

0.00862

AC:

AN:

116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0177

AC:

2700

AN:

152336

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1324

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00611

AC:

254

AN:

41576

American (AMR)

AF:

0.0195

AC:

298

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0549

AC:

265

AN:

4828

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0248

AC:

1685

AN:

68032

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0170

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 11 (1)

not provided (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.011

(source)

DANN

Benign

0.67

PhyloP100

-7.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over