Genetic Variant KLHL29:p.Thr118Met (chr2-23639206-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_052920.2(KLHL29):c.353C>T(p.Thr118Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,547,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KLHL29
NM_052920.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

KLHL29 (HGNC:29404): (kelch like family member 29)

KLHL29 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
KLHL29	NM_052920.2 link	c.353C>T	p.Thr118Met	missense_variant	Exon 4 of 14	ENST00000486442.6	NP_443152.1	Q96CT2-1
KLHL29	XM_006711929.4 link	c.353C>T	p.Thr118Met	missense_variant	Exon 3 of 13		XP_006711992.1	Q96CT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL29	ENST00000486442.6 link	c.353C>T	p.Thr118Met	missense_variant	Exon 4 of 14	5	NM_052920.2	ENSP00000420659.1		Q96CT2-1
KLHL29	ENST00000489446.1 link	n.434C>T		non_coding_transcript_exon_variant	Exon 3 of 4	1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000197

AC:

AN:

152324

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000452

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000194

AC:

AN:

1395256

Hom.:

Cov.:

AF XY:

0.0000189

AC XY:

AN XY:

688080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000956

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000213

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000533

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000390

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.353C>T (p.T118M) alteration is located in exon 4 (coding exon 2) of the KLHL29 gene. This alteration results from a C to T substitution at nucleotide position 353, causing the threonine (T) at amino acid position 118 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

0.41

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.028

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Vest4

0.64

MVP

0.91

ClinPred

0.68

GERP RS

4.9

Varity_R

0.16

gMVP

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over