1-9264154-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004285.4(H6PD):c.1661C>T(p.Pro554Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,612,930 control chromosomes in the GnomAD database, including 12,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P554P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.090 ( 845 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11500 hom. )

Consequence

H6PD
NM_004285.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.83

Publications

33 publications found

Variant links:

Genes affected

H6PD (HGNC:4795): (hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase) There are 2 forms of glucose-6-phosphate dehydrogenase. G form is X-linked and H form, encoded by this gene, is autosomally linked. This H form shows activity with other hexose-6-phosphates, especially galactose-6-phosphate, whereas the G form is specific for glucose-6-phosphate. Both forms are present in most tissues, but H form is not found in red cells. [provided by RefSeq, Jul 2008]

H6PD Gene-Disease associations (from GenCC):

cortisone reductase deficiency 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
cortisone reductase deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

H6PD 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 (MetaRNN=0.0016513467).

BP6

Variant 1-9264154-C-T is Benign according to our data. Variant chr1-9264154-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004285.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H6PD	NM_004285.4	MANE Select	c.1661C>T	p.Pro554Leu	missense	Exon 5 of 5	NP_004276.2
	H6PD	NM_001282587.2		c.1694C>T	p.Pro565Leu	missense	Exon 5 of 5	NP_001269516.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H6PD	ENST00000377403.7	TSL:1 MANE Select	c.1661C>T	p.Pro554Leu	missense	Exon 5 of 5	ENSP00000366620.2
	H6PD	ENST00000602477.1	TSL:1	c.1694C>T	p.Pro565Leu	missense	Exon 5 of 5	ENSP00000473348.1

Frequencies

GnomAD3 genomes

AF:

0.0906

AC:

13777

AN:

152126

Hom.:

845

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0904

Gnomad EAS

AF:

0.0615

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.0652

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.0890

GnomAD2 exomes

AF:

0.117

AC:

29045

AN:

248784

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.0200

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.0888

Gnomad EAS exome

AF:

0.0555

Gnomad FIN exome

AF:

0.0724

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.122

AC:

177688

AN:

1460686

Hom.:

11500

Cov.:

AF XY:

0.124

AC XY:

89860

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.0188

AC:

630

AN:

33474

American (AMR)

AF:

0.144

AC:

6421

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0889

AC:

2321

AN:

26118

East Asian (EAS)

AF:

0.0580

AC:

2302

AN:

39696

South Asian (SAS)

AF:

0.185

AC:

15925

AN:

86240

European-Finnish (FIN)

AF:

0.0761

AC:

4033

AN:

52974

Middle Eastern (MID)

AF:

0.151

AC:

873

AN:

5766

European-Non Finnish (NFE)

AF:

0.124

AC:

138271

AN:

1111366

Other (OTH)

AF:

0.115

AC:

6912

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9879

19758

29637

39516

49395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4992

9984

14976

19968

24960

<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:

0.0904

AC:

13766

AN:

152244

Hom.:

845

Cov.:

AF XY:

0.0902

AC XY:

6713

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0229

AC:

952

AN:

41564

American (AMR)

AF:

0.129

AC:

1971

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0904

AC:

314

AN:

3472

East Asian (EAS)

AF:

0.0616

AC:

319

AN:

5178

South Asian (SAS)

AF:

0.183

AC:

883

AN:

4822

European-Finnish (FIN)

AF:

0.0652

AC:

693

AN:

10622

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.123

AC:

8352

AN:

67968

Other (OTH)

AF:

0.0881

AC:

186

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

656

1312

1967

2623

3279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.113

Hom.:

4215

Bravo

AF:

0.0889

TwinsUK

AF:

0.121

AC:

450

ALSPAC

AF:

0.122

AC:

471

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.123

AC:

1054

ExAC

AF:

0.115

AC:

14010

Asia WGS

AF:

0.108

AC:

374

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.8

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.39

Sift

Benign

0.033

Sift4G

Benign

0.13

Polyphen

0.91

Vest4

0.13

MPC

0.11

ClinPred

0.020

GERP RS

4.8

Varity_R

0.080

gMVP

0.58

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over