chr1-9245250-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_004285.4(H6PD):c.316A>G(p.Ser106Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

H6PD
NM_004285.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.31

Publications

3 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18301085).

BP6

Variant 1-9245250-A-G is Benign according to our data. Variant chr1-9245250-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2225378.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000328 (50/152218) while in subpopulation AMR AF = 0.00157 (24/15280). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H6PD	NM_004285.4 link	c.316A>G	p.Ser106Gly	missense_variant	Exon 2 of 5	ENST00000377403.7	NP_004276.2	O95479-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H6PD	ENST00000377403.7 link	c.316A>G	p.Ser106Gly	missense_variant	Exon 2 of 5	1	NM_004285.4	ENSP00000366620.2		O95479-1
H6PD	ENST00000602477.1 link	c.349A>G	p.Ser117Gly	missense_variant	Exon 2 of 5	1		ENSP00000473348.1		O95479-2

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000290

AC:

AN:

251310

AF XY:

0.000280

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000148

AC:

216

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33478

American (AMR)

AF:

0.000693

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00379

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1112000

Other (OTH)

AF:

0.000447

AC:

AN:

60396

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

GnomAD4 genome

AF:

0.000328

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41456

American (AMR)

AF:

0.00157

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.316A>G (p.S106G) alteration is located in exon 2 (coding exon 1) of the H6PD gene. This alteration results from a A to G substitution at nucleotide position 316, causing the serine (S) at amino acid position 106 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.18

T;T

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

3.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;.

REVEL

Pathogenic

0.70

Sift

Benign

0.11

T;.

Sift4G

Uncertain

0.050

T;T

Polyphen

0.97

D;.

Vest4

0.68

MVP

0.97

MPC

0.32

ClinPred

0.052

GERP RS

5.3

Varity_R

0.61

gMVP

0.61

Mutation Taster

=67/33

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

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chr1-9245250-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over