dbSNP rs61751224: IMPDH1:c.1074+6G>T (chr7-128398408-C-A) – 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.1074+6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,612,340 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

IMPDH1
NM_000883.4 splice_region, intron

Scores

Splicing: ADA: 0.0009817

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.166

Publications

1 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: 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

IMPDH1 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=-0.76).

BP6

Variant 7-128398408-C-A is Benign according to our data. Variant chr7-128398408-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 774135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (337/152334) while in subpopulation AFR AF = 0.00551 (229/41586). AF 95% confidence interval is 0.00492. There are 1 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 337 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.1074+6G>T	splice_region intron	N/A	NP_000874.2
IMPDH1	NM_001102605.2		c.1044+6G>T	splice_region intron	N/A	NP_001096075.1	P20839-5
IMPDH1	NM_001142576.2		c.975+6G>T	splice_region intron	N/A	NP_001136048.1	P20839-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IMPDH1	ENST00000338791.11	TSL:2 MANE Select	c.1074+6G>T	splice_region intron	N/A	ENSP00000345096.6	P20839-6
IMPDH1	ENST00000348127.11	TSL:1	c.966+6G>T	splice_region intron	N/A	ENSP00000265385.8	P20839-3
IMPDH1	ENST00000955327.1		c.966+6G>T	splice_region intron	N/A	ENSP00000625386.1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

336

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000796

AC:

198

AN:

248588

AF XY:

0.000578

show subpopulations

Gnomad AFR exome

AF:

0.00587

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000241

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000395

AC:

576

AN:

1460006

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

726356

show subpopulations

African (AFR)

AF:

0.00454

AC:

152

AN:

33448

American (AMR)

AF:

0.00230

AC:

103

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52768

Middle Eastern (MID)

AF:

0.00146

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.000214

AC:

238

AN:

1111268

Other (OTH)

AF:

0.00113

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152334

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00551

AC:

229

AN:

41586

American (AMR)

AF:

0.00509

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68024

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00317

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Benign/Likely 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

-0.76

CADD

Benign

6.9

(source)

DANN

Benign

0.71

PhyloP100

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00098

dbscSNV1_RF

Benign

0.018

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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