NM_004285.4:c.1358G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_004285.4(H6PD):c.1358G>C(p.Arg453Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

H6PD
NM_004285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0830

Publications

52 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08244187).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000698 (102/1461606) while in subpopulation SAS AF = 0.000696 (60/86258). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAdExome4. There are 72 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H6PD	NM_004285.4	MANE Select	c.1358G>C	p.Arg453Pro	missense	Exon 5 of 5	NP_004276.2
	H6PD	NM_001282587.2		c.1391G>C	p.Arg464Pro	missense	Exon 5 of 5	NP_001269516.1	O95479-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H6PD	ENST00000377403.7	TSL:1 MANE Select	c.1358G>C	p.Arg453Pro	missense	Exon 5 of 5	ENSP00000366620.2	O95479-1
H6PD	ENST00000602477.1	TSL:1	c.1391G>C	p.Arg464Pro	missense	Exon 5 of 5	ENSP00000473348.1	O95479-2
H6PD	ENST00000891474.1		c.1358G>C	p.Arg453Pro	missense	Exon 5 of 5	ENSP00000561533.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

250914

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111940

Other (OTH)

AF:

0.0000662

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41540

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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:

0.00

Hom.:

12962

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Benign

2.5

(source)

DANN

Benign

0.74

DEOGEN2

Uncertain

0.49

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.082

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

PhyloP100

-0.083

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.29

Sift

Benign

0.21

Sift4G

Benign

0.23

Polyphen

0.28

Vest4

0.21

MutPred

0.58

Gain of glycosylation at S450 (P = 0.1431)

MVP

0.81

MPC

0.18

ClinPred

0.032

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.71

Mutation Taster

=74/26

polymorphism

(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

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