18-32769955-C-T

Position:

• chr18-32769955-C-T

Variant summary

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

The NM_020805.3(KLHL14):​c.637G>A​(p.Val213Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL14 NM_020805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

Genes affected

KLHL14 (HGNC:29266): (kelch like family member 14) The protein encoded by this gene is a member of the Kelch-like gene family, whose members contain a BTB/POZ domain, a BACK domain, and several Kelch domains. The encoded protein possesses six Kelch domains and localizes to the endoplasmic reticulum, where it interacts with torsin-1A. [provided by RefSeq, Sep 2015]

ENSG00000228835 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL14	NM_020805.3	c.637G>A	p.Val213Met	missense_variant	2/9	ENST00000359358.9	NP_065856.1
KLHL14	XM_047437684.1	c.637G>A	p.Val213Met	missense_variant	2/4		XP_047293640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL14	ENST00000359358.9	c.637G>A	p.Val213Met	missense_variant	2/9	1	NM_020805.3	ENSP00000352314.4
KLHL14	ENST00000358095.4	c.637G>A	p.Val213Met	missense_variant	2/4	1		ENSP00000350808.4
ENSG00000228835	ENST00000426194.1	n.161C>T		non_coding_transcript_exon_variant	1/4	5
KLHL14	ENST00000583263.1	c.*36G>A		downstream_gene_variant		2		ENSP00000463803.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 31

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

Jun 19, 2024

The c.637G>A (p.V213M) alteration is located in exon 2 (coding exon 1) of the KLHL14 gene. This alteration results from a G to A substitution at nucleotide position 637, causing the valine (V) at amino acid position 213 to be replaced by a methionine (M). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.40	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.055	T;D
Polyphen		1.0	D;.
Vest4		0.61
MutPred		0.56		Gain of catalytic residue at V213 (P = 0.0097);Gain of catalytic residue at V213 (P = 0.0097);
MVP		0.77
MPC		1.2
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.64

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: chr18-30349918;