18-32680438-G-C

Position:

• chr18-32680438-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020805.3(KLHL14):​c.1400C>G​(p.Ala467Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,688 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL14 NM_020805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

ENSG00000285095 (HGNC:):

ACMG classification

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, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL14	NM_020805.3	c.1400C>G	p.Ala467Gly	missense_variant	6/9	ENST00000359358.9	NP_065856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL14	ENST00000359358.9	c.1400C>G	p.Ala467Gly	missense_variant	6/9	1	NM_020805.3	ENSP00000352314.4
ENSG00000285095	ENST00000646805.1	n.817-56913G>C		intron_variant
ENSG00000285095	ENST00000654761.1	n.185-56913G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 22, 2023

The c.1400C>G (p.A467G) alteration is located in exon 6 (coding exon 5) of the KLHL14 gene. This alteration results from a C to G substitution at nucleotide position 1400, causing the alanine (A) at amino acid position 467 to be replaced by a glycine (G). 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	0.22
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.74		Gain of disorder (P = 0.0934);
MVP		0.89
MPC		1.3
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.59
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1598545274; hg19: chr18-30260401;