Genetic Variant NM_000883.4:c.255-531G>A (chr7-128406396-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000883.4(IMPDH1):c.255-531G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 149,730 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 48 hom., cov: 29)

Consequence

IMPDH1
NM_000883.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0680

Publications

0 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):

inherited retinal dystrophy
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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IMPDH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1939/149730) while in subpopulation AFR AF = 0.0453 (1834/40500). AF 95% confidence interval is 0.0436. There are 48 homozygotes in GnomAd4. There are 914 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 1939 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPDH1	NM_000883.4 link	c.255-531G>A		intron_variant	Intron 3 of 16	ENST00000338791.11	NP_000874.2	P20839-6B3KRZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPDH1	ENST00000338791.11 link	c.255-531G>A		intron_variant	Intron 3 of 16	2	NM_000883.4	ENSP00000345096.6		P20839-6

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1938

AN:

149608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00539

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000637

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000119

Gnomad OTH

AF:

0.00678

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0129

AC:

1939

AN:

149730

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

914

AN XY:

73066

show subpopulations

African (AFR)

AF:

0.0453

AC:

1834

AN:

40500

American (AMR)

AF:

0.00538

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4982

South Asian (SAS)

AF:

0.000424

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000119

AC:

AN:

67434

Other (OTH)

AF:

0.00670

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00310

Hom.:

Bravo

AF:

0.0148

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.1

(source)

DANN

Benign

0.60

PhyloP100

-0.068

PromoterAI

-0.014

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over