Genetic Variant G6PD:c.120+7A>C (chrX-154546029-T-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_001360016.2(G6PD):c.120+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,207,809 control chromosomes in the GnomAD database, including 28 homozygotes. There are 1,305 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., 53 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 27 hom. 1252 hem. )

Consequence

G6PD
NM_001360016.2 splice_region, intron

Scores

Splicing: ADA: 0.00003388

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0680

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-154546029-T-G is Benign according to our data. Variant chrX-154546029-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368103.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00101 (112/110772) while in subpopulation SAS AF = 0.0397 (104/2622). AF 95% confidence interval is 0.0335. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 53 XL geneVariant has number of hemizygotes 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+7A>C	splice_region intron	N/A	NP_001346945.1	A0A384NL00
G6PD	NM_000402.4		c.210+7A>C	splice_region intron	N/A	NP_000393.4	P11413-3
G6PD	NM_001042351.3		c.120+7A>C	splice_region 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+7A>C	splice_region intron	N/A	ENSP00000377192.3	P11413-1
IKBKG	ENST00000618670.4	TSL:1	c.189+3577T>G	intron	N/A	ENSP00000483825.1	Q9Y6K9-2
IKBKG	ENST00000612051.1	TSL:1	n.124+3642T>G	intron	N/A	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

111

AN:

110720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0392

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00426

AC:

777

AN:

182414

AF XY:

0.00682

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000489

Gnomad OTH exome

AF:

0.00243

GnomAD4 exome

AF:

0.00198

AC:

2175

AN:

1097037

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

1252

AN XY:

362549

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30188

South Asian (SAS)

AF:

0.0375

AC:

2032

AN:

54132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39955

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

841622

Other (OTH)

AF:

0.00235

AC:

108

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00101

AC:

112

AN:

110772

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

AN XY:

32990

show subpopulations

African (AFR)

AF:

0.000263

AC:

AN:

30466

American (AMR)

AF:

0.00

AC:

AN:

10402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3532

South Asian (SAS)

AF:

0.0397

AC:

104

AN:

2622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5847

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52864

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000288

Hom.:

Bravo

AF:

0.000276

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)

G6PD deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.1

(source)

DANN

Benign

0.71

PhyloP100

0.068

PromoterAI

0.0055

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0020

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