1-9245386-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004285.4(H6PD):c.452A>C(p.Asp151Ala) variant causes a missense change. The variant allele was found at a frequency of 0.137 in 1,614,012 control chromosomes in the GnomAD database, including 16,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (1128 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15267 hom.)
• Consequence: H6PD NM_004285.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024963915).
• BP6: Variant 1-9245386-A-C is Benign according to our data. Variant chr1-9245386-A-C is described in ClinVar as [Benign]. Clinvar id is 1601522.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H6PD	NM_004285.4	c.452A>C	p.Asp151Ala	missense_variant	2/5	ENST00000377403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H6PD	ENST00000377403.7	c.452A>C	p.Asp151Ala	missense_variant	2/5	1	NM_004285.4	P1
H6PD	ENST00000602477.1	c.485A>C	p.Asp162Ala	missense_variant	2/5	1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15926 AN: 152124 Hom.: 1128 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.118 AC: 29595 AN: 251168 Hom.: 2159 AF XY: 0.125 AC XY: 17023 AN XY: 135824

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.140 AC: 204862 AN: 1461770 Hom.: 15267 Cov.: 36 AF XY: 0.142 AC XY: 103089 AN XY: 727184

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.0834

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.105 AC: 15917 AN: 152242 Hom.: 1128 Cov.: 32 AF XY: 0.103 AC XY: 7682 AN XY: 74446

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.118

Alfa AF: 0.140 Hom.: 2627

Bravo AF: 0.0986

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.139 AC: 536

ESP6500AA AF: 0.0272 AC: 120

ESP6500EA AF: 0.152 AC: 1307

ExAC AF: 0.120 AC: 14571

Asia WGS AF: 0.0650 AC: 229 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.160

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.00021	P
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.041	D;.
Sift4G	Benign	0.61	T;T
Polyphen		0.70	P;.
Vest4		0.17
MPC		0.23
ClinPred		0.034	T
GERP RS		4.2
Varity_R		0.32
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs34603401; hg19: chr1-9305445;