X-154546029-T-C

Variant names:

• chrX-154546029-T-C
• rs369904290
• NM_001360016.2:c.120+7A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001360016.2(G6PD):​c.120+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: G6PD NM_001360016.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003076
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0680
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-154546029-T-C is Benign according to our data. Variant chrX-154546029-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1128354.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.120+7A>G		splice_region intron	N/A	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.210+7A>G		splice_region intron	N/A	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.120+7A>G		splice_region intron	N/A	NP_001035810.1	P11413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.120+7A>G		splice_region intron	N/A	ENSP00000377192.3	P11413-1
	IKBKG	ENST00000618670.4	TSL:1	c.189+3577T>C		intron	N/A	ENSP00000483825.1	Q9Y6K9-2
	IKBKG	ENST00000612051.1	TSL:1	n.124+3642T>C		intron	N/A	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097037 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362549

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39955

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841622

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		0.068
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0040
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: rs369904290; hg19: chrX-153774244;