X-23988260-GAC-TAT

Variant names:

• chrX-23988260-GAC-TAT
• NM_030624.3:c.1474_1476delGTCinsATA
• KLHL15 p.Val492Ile

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_030624.3(KLHL15):​c.1474_1476delGTCinsATA​(p.Val492Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: KLHL15 NM_030624.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

KLHL15 (HGNC:29347): (kelch like family member 15) This gene encodes a member of the kelch-like family of proteins that share a common domain structure consisting of an N-terminal broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger domain and C-terminal kelch repeat motifs. The encoded protein may be involved in protein ubiquitination and cytoskeletal organization. [provided by RefSeq, Apr 2009]

KLHL15 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 103

  Inheritance: AD, XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_030624.3 (KLHL15) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030624.3. 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
	KLHL15	NM_030624.3	MANE Select	c.1474_1476delGTCinsATA	p.Val492Ile	missense	N/A	NP_085127.2	Q96M94

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL15	ENST00000328046.8	TSL:2 MANE Select	c.1474_1476delGTCinsATA	p.Val492Ile	missense	N/A	ENSP00000332791.8	Q96M94
	KLHL15	ENST00000692681.1		c.1474_1476delGTCinsATA	p.Val492Ile	missense	N/A	ENSP00000510696.1	A0A8I5QJW5
	KLHL15	ENST00000684871.1		c.1474_1476delGTCinsATA	p.Val492Ile	missense	N/A	ENSP00000509774.1	Q96M94

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-24006377;