1-9245250-A-G

Position:

• chr1-9245250-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004285.4(H6PD):​c.316A>G​(p.Ser106Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: H6PD NM_004285.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.31

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18301085).
• BP6: Variant 1-9245250-A-G is Benign according to our data. Variant chr1-9245250-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2225378.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H6PD	NM_004285.4	c.316A>G	p.Ser106Gly	missense_variant	2/5	ENST00000377403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H6PD	ENST00000377403.7	c.316A>G	p.Ser106Gly	missense_variant	2/5	1	NM_004285.4	P1
H6PD	ENST00000602477.1	c.349A>G	p.Ser117Gly	missense_variant	2/5	1

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000290 AC: 73 AN: 251310 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135858

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461844 Hom.: 0 Cov.: 34 AF XY: 0.000149 AC XY: 108 AN XY: 727220

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74370

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.316A>G (p.S106G) alteration is located in exon 2 (coding exon 1) of the H6PD gene. This alteration results from a A to G substitution at nucleotide position 316, causing the serine (S) at amino acid position 106 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;.
REVEL	Pathogenic	0.70
Sift	Benign	0.11	T;.
Sift4G	Uncertain	0.050	T;T
Polyphen		0.97	D;.
Vest4		0.68
MVP		0.97
MPC		0.32
ClinPred		0.052	T
GERP RS		5.3
Varity_R		0.61
gMVP		0.61

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: rs148725451; hg19: chr1-9305309;