Variant 18-32741970-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020805.3(KLHL14):c.1027C>A(p.Gln343Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHL14
NM_020805.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

Variant links:

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]

KLHL14 links:

ENSG00000285095 (HGNC:):

ENSG00000285095 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL14	NM_020805.3 linkuse as main transcript	c.1027C>A	p.Gln343Lys	missense_variant	3/9	ENST00000359358.9	NP_065856.1	Q9P2G3-1
KLHL14	XM_047437684.1 linkuse as main transcript	c.1027C>A	p.Gln343Lys	missense_variant	3/4		XP_047293640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL14	ENST00000359358.9 linkuse as main transcript	c.1027C>A	p.Gln343Lys	missense_variant	3/9	1	NM_020805.3	ENSP00000352314.4	Q9P2G3-1
KLHL14	ENST00000358095.4 linkuse as main transcript	c.1027C>A	p.Gln343Lys	missense_variant	3/4	1		ENSP00000350808.4	Q9P2G3-2
ENSG00000285095	ENST00000646805.1 linkuse as main transcript	n.2297-882G>T		intron_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726426

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1027C>A (p.Q343K) alteration is located in exon 3 (coding exon 2) of the KLHL14 gene. This alteration results from a C to A substitution at nucleotide position 1027, causing the glutamine (Q) at amino acid position 343 to be replaced by a lysine (K). 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

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.030

T;.

Eigen

Uncertain

0.56

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.0

N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.29

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.68

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.71

P;.

Vest4

0.88

MutPred

0.55

Gain of methylation at Q343 (P = 0.0113);Gain of methylation at Q343 (P = 0.0113);

MVP

0.80

MPC

0.62

ClinPred

0.84

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.67

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over