chr1-9263851-G-A

Position:

• chr1-9263851-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004285.4(H6PD):​c.1358G>A​(p.Arg453Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,613,468 control chromosomes in the GnomAD database, including 55,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8155 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47450 hom.)
• Consequence: H6PD NM_004285.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.0830

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.1385164E-4).
• BP6: Variant 1-9263851-G-A is Benign according to our data. Variant chr1-9263851-G-A is described in ClinVar as [Benign]. Clinvar id is 16131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H6PD	NM_004285.4	c.1358G>A	p.Arg453Gln	missense_variant	5/5	ENST00000377403.7	NP_004276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H6PD	ENST00000377403.7	c.1358G>A	p.Arg453Gln	missense_variant	5/5	1	NM_004285.4	ENSP00000366620.2
H6PD	ENST00000602477.1	c.1391G>A	p.Arg464Gln	missense_variant	5/5	1		ENSP00000473348.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47384 AN: 152016 Hom.: 8121 Cov.: 33

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.303

GnomAD3 exomes AF: 0.284 AC: 71377 AN: 250914 Hom.: 11094 AF XY: 0.277 AC XY: 37592 AN XY: 135722

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.472

Gnomad SAS exome AF: 0.278

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.248 AC: 362167 AN: 1461334 Hom.: 47450 Cov.: 38 AF XY: 0.248 AC XY: 180035 AN XY: 727004

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.312 AC: 47458 AN: 152134 Hom.: 8155 Cov.: 33 AF XY: 0.311 AC XY: 23157 AN XY: 74388

Gnomad4 AFR AF: 0.458

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.303

Alfa AF: 0.242 Hom.: 8065

Bravo AF: 0.324

TwinsUK AF: 0.231 AC: 858

ALSPAC AF: 0.242 AC: 932

ESP6500AA AF: 0.458 AC: 2017

ESP6500EA AF: 0.229 AC: 1971

ExAC AF: 0.284 AC: 34526

Asia WGS AF: 0.406 AC: 1409 AN: 3478

EpiCase AF: 0.235

EpiControl AF: 0.240

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	This variant is associated with the following publications: (PMID: 12858176, 21050867, 20981092, 22306327) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cortisone reductase deficiency 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	2.2
DANN	Benign	0.67
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.13	T;T
MetaRNN	Benign	0.00051	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.48	N;.
REVEL	Benign	0.18
Sift	Benign	0.57	T;.
Sift4G	Benign	0.57	T;T
Polyphen		0.0010	B;.
Vest4		0.049
MPC		0.12
ClinPred		0.00059	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.36

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: rs6688832; hg19: chr1-9323910; COSMIC: COSV66231098; COSMIC: COSV66231098;