X-87518236-T-G

Position:

• chrX-87518236-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019117.5(KLHL4):​c.343T>G​(p.Leu115Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: KLHL4 NM_019117.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

Genes affected

KLHL4 (HGNC:6355): (kelch like family member 4) This gene encodes a member of the kelch family of proteins, which are characterized by kelch repeat motifs and a POZ/BTB protein-binding domain. It is thought that kelch repeats are actin binding domains. However, the specific function of this protein has not been determined. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

KLHL4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10579863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5	c.343T>G	p.Leu115Val	missense_variant	1/11	ENST00000373119.9	NP_061990.2
KLHL4	NM_057162.3	c.343T>G	p.Leu115Val	missense_variant	1/11		NP_476503.1
KLHL4	XR_938403.3	n.435T>G		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL4	ENST00000373119.9	c.343T>G	p.Leu115Val	missense_variant	1/11	1	NM_019117.5	ENSP00000362211.4
KLHL4	ENST00000373114.4	c.343T>G	p.Leu115Val	missense_variant	1/11	1		ENSP00000362206.4
KLHL4	ENST00000652270.1	n.343T>G		non_coding_transcript_exon_variant	1/12			ENSP00000498718.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.343T>G (p.L115V) alteration is located in exon 1 (coding exon 1) of the KLHL4 gene. This alteration results from a T to G substitution at nucleotide position 343, causing the leucine (L) at amino acid position 115 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.41
DEOGEN2	Benign	0.021	T;.
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.18
Sift	Benign	0.23	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0030	B;B
Vest4		0.082
MutPred		0.32		Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);
MVP		0.66
MPC		0.32
ClinPred		0.081	T
GERP RS		3.9
Varity_R		0.24
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-86773239;