dbSNP rs144918804: G6PD:c.120+235G>A (chrX-154545801-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBS1BS2_Supporting

The NM_001360016.2(G6PD):c.120+235G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.031 ( 64 hom., 694 hem., cov: 19)

Exomes 𝑓: 0.036 ( 170 hom. 2814 hem. )

Consequence

G6PD
NM_001360016.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.301

Publications

2 publications found

Variant links:

Genes affected

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

G6PD links:

IKBKG (HGNC:5961): (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. A pseudogene highly similar to this locus is located in an adjacent region of the X chromosome. [provided by RefSeq, Mar 2016]

IKBKG Gene-Disease associations (from GenCC):

ectodermal dysplasia and immunodeficiency 1
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
IKBKG-related immunodeficiency with or without ectodermal dysplasia
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
incontinentia pigmenti
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet
ectodermal dysplasia and immune deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency 33
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

IKBKG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant X-154545801-C-T is Benign according to our data. Variant chrX-154545801-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228119.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0307 (3230/105287) while in subpopulation NFE AF = 0.0491 (2497/50885). AF 95% confidence interval is 0.0475. There are 64 homozygotes in GnomAd4. There are 694 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 64 XL geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
G6PD	NM_001360016.2	MANE Select	c.120+235G>A	intron	N/A	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.210+235G>A	intron	N/A	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.120+235G>A	intron	N/A	NP_001035810.1	P11413-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
G6PD	ENST00000393562.10	TSL:1 MANE Select	c.120+235G>A	intron	N/A	ENSP00000377192.3	P11413-1
IKBKG	ENST00000618670.4	TSL:1	c.189+3349C>T	intron	N/A	ENSP00000483825.1	Q9Y6K9-2
IKBKG	ENST00000612051.1	TSL:1	n.124+3414C>T	intron	N/A	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

3228

AN:

105242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00599

Gnomad AMI

AF:

0.0359

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.000586

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0484

Gnomad MID

AF:

0.0173

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.0180

GnomAD4 exome

AF:

0.0363

AC:

9319

AN:

256841

Hom.:

170

Cov.:

AF XY:

0.0365

AC XY:

2814

AN XY:

77127

show subpopulations

African (AFR)

AF:

0.00620

AC:

AN:

7909

American (AMR)

AF:

0.00858

AC:

100

AN:

11660

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

133

AN:

7425

East Asian (EAS)

AF:

0.00

AC:

AN:

16320

South Asian (SAS)

AF:

0.0296

AC:

763

AN:

25802

European-Finnish (FIN)

AF:

0.0485

AC:

691

AN:

14248

Middle Eastern (MID)

AF:

0.0318

AC:

AN:

1005

European-Non Finnish (NFE)

AF:

0.0447

AC:

7039

AN:

157412

Other (OTH)

AF:

0.0340

AC:

512

AN:

15060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

316

632

947

1263

1579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0307

AC:

3230

AN:

105287

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

694

AN XY:

27997

show subpopulations

African (AFR)

AF:

0.00598

AC:

171

AN:

28607

American (AMR)

AF:

0.0124

AC:

123

AN:

9958

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

2573

East Asian (EAS)

AF:

0.000588

AC:

AN:

3402

South Asian (SAS)

AF:

0.0244

AC:

AN:

2256

European-Finnish (FIN)

AF:

0.0484

AC:

259

AN:

5351

Middle Eastern (MID)

AF:

0.0192

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0491

AC:

2497

AN:

50885

Other (OTH)

AF:

0.0178

AC:

AN:

1406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0440

Hom.:

233

Bravo

AF:

0.0270

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.6

(source)

DANN

Benign

0.48

PhyloP100

-0.30

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over