chr1-9264512-T-C

Variant names:

• chr1-9264512-T-C
• rs9434742
• NM_004285.4:c.2019T>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.2019T>C​(p.Tyr673Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,612,808 control chromosomes in the GnomAD database, including 130,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13577 hom., cov: 33)
  • Exomes 𝑓: 0.40 (117237 hom.)
• Consequence: H6PD NM_004285.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.55
• Publications: 19 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=-0.95).
• BP6: Variant 1-9264512-T-C is Benign according to our data. Variant chr1-9264512-T-C is described in ClinVar as Benign. ClinVar VariationId is 1540015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004285.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H6PD	NM_004285.4	MANE Select	c.2019T>C	p.Tyr673Tyr	synonymous	Exon 5 of 5	NP_004276.2
	H6PD	NM_001282587.2		c.2052T>C	p.Tyr684Tyr	synonymous	Exon 5 of 5	NP_001269516.1	O95479-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H6PD	ENST00000377403.7	TSL:1 MANE Select	c.2019T>C	p.Tyr673Tyr	synonymous	Exon 5 of 5	ENSP00000366620.2	O95479-1
	H6PD	ENST00000602477.1	TSL:1	c.2052T>C	p.Tyr684Tyr	synonymous	Exon 5 of 5	ENSP00000473348.1	O95479-2
	H6PD	ENST00000891474.1		c.2019T>C	p.Tyr673Tyr	synonymous	Exon 5 of 5	ENSP00000561533.1

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63544 AN: 151990 Hom.: 13564 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.402

GnomAD2 exomes AF: 0.412 AC: 102994 AN: 250056 AF XY: 0.413

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.526

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.397 AC: 579938 AN: 1460700 Hom.: 117237 Cov.: 46 AF XY: 0.400 AC XY: 290567 AN XY: 726670

African (AFR) AF: 0.493 AC: 16498 AN: 33472

American (AMR) AF: 0.515 AC: 23030 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11036 AN: 26128

East Asian (EAS) AF: 0.135 AC: 5368 AN: 39696

South Asian (SAS) AF: 0.500 AC: 43148 AN: 86244

European-Finnish (FIN) AF: 0.343 AC: 18021 AN: 52596

Middle Eastern (MID) AF: 0.528 AC: 3043 AN: 5768

European-Non Finnish (NFE) AF: 0.392 AC: 435936 AN: 1111702

Other (OTH) AF: 0.395 AC: 23858 AN: 60370

GnomAD4 genome AF: 0.418 AC: 63590 AN: 152108 Hom.: 13577 Cov.: 33 AF XY: 0.417 AC XY: 31040 AN XY: 74356

African (AFR) AF: 0.489 AC: 20267 AN: 41488

American (AMR) AF: 0.442 AC: 6756 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1483 AN: 3464

East Asian (EAS) AF: 0.154 AC: 797 AN: 5164

South Asian (SAS) AF: 0.492 AC: 2371 AN: 4822

European-Finnish (FIN) AF: 0.337 AC: 3573 AN: 10600

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.396 AC: 26901 AN: 67962

Other (OTH) AF: 0.405 AC: 854 AN: 2110

Alfa AF: 0.411 Hom.: 20563

Bravo AF: 0.425

Asia WGS AF: 0.334 AC: 1164 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cortisone reductase deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.085
DANN	Benign	0.26
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9434742; hg19: chr1-9324571; COSMIC: COSV66230556; COSMIC: COSV66230556;