chr1-9246974-G-A

Variant names:

• chr1-9246974-G-A
• rs7524046
• NM_004285.4:c.636G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004285.4(H6PD):​c.636G>A​(p.Ala212Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,606,590 control chromosomes in the GnomAD database, including 46,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3679 hom., cov: 31)
  • Exomes 𝑓: 0.24 (43179 hom.)
• Consequence: H6PD NM_004285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.424
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-9246974-G-A is Benign according to our data. Variant chr1-9246974-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.424 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H6PD	NM_004285.4	c.636G>A	p.Ala212Ala	synonymous_variant	Exon 3 of 5	ENST00000377403.7	NP_004276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H6PD	ENST00000377403.7	c.636G>A	p.Ala212Ala	synonymous_variant	Exon 3 of 5	1	NM_004285.4	ENSP00000366620.2
H6PD	ENST00000602477.1	c.669G>A	p.Ala223Ala	synonymous_variant	Exon 3 of 5	1		ENSP00000473348.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32048 AN: 151970 Hom.: 3678 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.226 AC: 56934 AN: 251388 AF XY: 0.225

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.239 AC: 347434 AN: 1454502 Hom.: 43179 Cov.: 31 AF XY: 0.236 AC XY: 171090 AN XY: 724012

African (AFR) AF: 0.156 AC: 5197 AN: 33344

American (AMR) AF: 0.236 AC: 10562 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4762 AN: 26088

East Asian (EAS) AF: 0.400 AC: 15858 AN: 39638

South Asian (SAS) AF: 0.152 AC: 13107 AN: 86136

European-Finnish (FIN) AF: 0.162 AC: 8670 AN: 53380

Middle Eastern (MID) AF: 0.214 AC: 1231 AN: 5754

European-Non Finnish (NFE) AF: 0.248 AC: 273864 AN: 1105300

Other (OTH) AF: 0.236 AC: 14183 AN: 60150

GnomAD4 genome AF: 0.211 AC: 32058 AN: 152088 Hom.: 3679 Cov.: 31 AF XY: 0.208 AC XY: 15487 AN XY: 74350

African (AFR) AF: 0.155 AC: 6429 AN: 41502

American (AMR) AF: 0.231 AC: 3530 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3472

East Asian (EAS) AF: 0.429 AC: 2205 AN: 5136

South Asian (SAS) AF: 0.167 AC: 805 AN: 4830

European-Finnish (FIN) AF: 0.151 AC: 1605 AN: 10606

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16080 AN: 67956

Other (OTH) AF: 0.227 AC: 480 AN: 2112

Alfa AF: 0.233 Hom.: 12883

Bravo AF: 0.220

Asia WGS AF: 0.245 AC: 851 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cortisone reductase deficiency 1 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.68
DANN	Benign	0.70
PhyloP100		-0.42
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7524046; hg19: chr1-9307033; COSMIC: COSV66230512;