X-46471140-AGA-T

Position:

• chrX-46471140-AGA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001129899.2(KRBOX4):​c.254-2_254delAGAinsT​(p.Asp85fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: KRBOX4 NM_001129899.2 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.590

Genes affected

KRBOX4 (HGNC:26007): (KRAB box domain containing 4) This encodes a zinc finger protein with an N-terminal KRAB (Kruppel-associated) domain found in transcriptional repressors. This gene is located in a region of the X chromosome thought to be involved in nonsyndromic X-linked cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2	c.254-1610_254-1608delAGAinsT		intron_variant		ENST00000344302.9	NP_001123370.1
KRBOX4	NM_017776.3	c.239-1610_239-1608delAGAinsT		intron_variant			NP_060246.2
KRBOX4	NM_001129899.2	c.254-2_254delAGAinsT	p.Asp85fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	6/7		NP_001123371.1
KRBOX4	NM_001129900.2	c.239-2_239delAGAinsT	p.Asp80fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	6/7		NP_001123372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRBOX4	ENST00000344302.9	c.254-1610_254-1608delAGAinsT		intron_variant		2	NM_001129898.2	ENSP00000345797.4

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Uncertain significance and reported on 09-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-46330575;