X-154545836-CAAAAAAAAAAA-CAAAAAA

Variant names:

• chrX-154545836-CAAAAA-C
• rs781893284
• NM_001360016.2:c.120+195_120+199delTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001360016.2(G6PD):​c.120+195_120+199delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 281,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0017 (0 hom. 1 hem.)
• Consequence: G6PD NM_001360016.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• 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: Uncertain_significance. The variant received 0 ACMG points.

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+195_120+199delTTTTT		intron	N/A	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.210+195_210+199delTTTTT		intron	N/A	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.120+195_120+199delTTTTT		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+195_120+199delTTTTT		intron	N/A	ENSP00000377192.3	P11413-1
	IKBKG	ENST00000618670.4	TSL:1	c.189+3400_189+3404delAAAAA		intron	N/A	ENSP00000483825.1	Q9Y6K9-2
	IKBKG	ENST00000612051.1	TSL:1	n.124+3465_124+3469delAAAAA		intron	N/A	ENSP00000480431.1	A0A087WWQ9

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 1 AN: 37122 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00167 AC: 408 AN: 244403 Hom.: 0 AF XY: 0.0000134 AC XY: 1 AN XY: 74577

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00126 AC: 9 AN: 7136

American (AMR) AF: 0.00242 AC: 27 AN: 11173

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 14 AN: 6663

East Asian (EAS) AF: 0.00221 AC: 33 AN: 14954

South Asian (SAS) AF: 0.000649 AC: 15 AN: 23116

European-Finnish (FIN) AF: 0.00186 AC: 27 AN: 14502

Middle Eastern (MID) AF: 0.00112 AC: 1 AN: 894

European-Non Finnish (NFE) AF: 0.00172 AC: 262 AN: 152323

Other (OTH) AF: 0.00147 AC: 20 AN: 13642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000269 AC: 1 AN: 37122 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 7794

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000970 AC: 1 AN: 10309

American (AMR) AF: 0.00 AC: 0 AN: 3034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 934

East Asian (EAS) AF: 0.00 AC: 0 AN: 1319

South Asian (SAS) AF: 0.00 AC: 0 AN: 904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18475

Other (OTH) AF: 0.00 AC: 0 AN: 460

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781893284; hg19: chrX-153774051;