Genetic Variant NM_004285.4:c.415A>C (chr1-9245349-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004285.4(H6PD):c.415A>C(p.Ile139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. I139V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

H6PD
NM_004285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23342174).

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.415A>C	p.Ile139Leu	missense	Exon 2 of 5	NP_004276.2
	H6PD	NM_001282587.2		c.448A>C	p.Ile150Leu	missense	Exon 2 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.415A>C	p.Ile139Leu	missense	Exon 2 of 5	ENSP00000366620.2	O95479-1
H6PD	ENST00000602477.1	TSL:1	c.448A>C	p.Ile150Leu	missense	Exon 2 of 5	ENSP00000473348.1	O95479-2
H6PD	ENST00000891474.1		c.415A>C	p.Ile139Leu	missense	Exon 2 of 5	ENSP00000561533.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

7.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.38

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.74

M_CAP

Benign

0.024

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.25

PhyloP100

1.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.10

REVEL

Uncertain

0.32

Sift

Benign

0.57

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.29

MutPred

0.53

Gain of methylation at R138 (P = 0.1369)

MVP

0.77

MPC

0.11

ClinPred

0.096

GERP RS

1.4

Varity_R

0.052

gMVP

0.52

Mutation Taster

=88/12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over