1-9247079-T-C

Variant names:

• chr1-9247079-T-C
• rs11121350
• NM_004285.4:c.741T>C

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.741T>C​(p.Ala247Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,595,002 control chromosomes in the GnomAD database, including 49,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5249 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44458 hom.)
• Consequence: H6PD NM_004285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.94
• Publications: 12 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=-0.93).
• BP6: Variant 1-9247079-T-C is Benign according to our data. Variant chr1-9247079-T-C is described in ClinVar as [Benign]. Clinvar id is 1288974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H6PD	NM_004285.4	c.741T>C	p.Ala247Ala	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.741T>C	p.Ala247Ala	synonymous_variant	Exon 3 of 5	1	NM_004285.4	ENSP00000366620.2
H6PD	ENST00000602477.1	c.774T>C	p.Ala258Ala	synonymous_variant	Exon 3 of 5	1		ENSP00000473348.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38640 AN: 151968 Hom.: 5237 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.239 AC: 60111 AN: 251250 AF XY: 0.234

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.244 AC: 351534 AN: 1442916 Hom.: 44458 Cov.: 27 AF XY: 0.241 AC XY: 172925 AN XY: 718986

African (AFR) AF: 0.305 AC: 10102 AN: 33070

American (AMR) AF: 0.245 AC: 10939 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4754 AN: 26026

East Asian (EAS) AF: 0.425 AC: 16817 AN: 39554

South Asian (SAS) AF: 0.153 AC: 13163 AN: 85956

European-Finnish (FIN) AF: 0.163 AC: 8681 AN: 53392

Middle Eastern (MID) AF: 0.220 AC: 1261 AN: 5724

European-Non Finnish (NFE) AF: 0.248 AC: 271090 AN: 1094782

Other (OTH) AF: 0.247 AC: 14727 AN: 59720

GnomAD4 genome AF: 0.254 AC: 38697 AN: 152086 Hom.: 5249 Cov.: 32 AF XY: 0.250 AC XY: 18624 AN XY: 74366

African (AFR) AF: 0.304 AC: 12611 AN: 41486

American (AMR) AF: 0.248 AC: 3786 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3468

East Asian (EAS) AF: 0.445 AC: 2294 AN: 5152

South Asian (SAS) AF: 0.168 AC: 812 AN: 4824

European-Finnish (FIN) AF: 0.151 AC: 1596 AN: 10592

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16136 AN: 67962

Other (OTH) AF: 0.255 AC: 537 AN: 2110

Alfa AF: 0.248 Hom.: 4047

Bravo AF: 0.269

Asia WGS AF: 0.266 AC: 924 AN: 3478

EpiCase AF: 0.238

EpiControl AF: 0.251

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	-0.93
CADD	Benign	0.0030
DANN	Benign	0.28
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11121350; hg19: chr1-9307138; COSMIC: COSV66230518;