Genetic Variant KLHL29:p.Arg3Gln (chr2-23562204-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_052920.2(KLHL29):c.8G>A(p.Arg3Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,550,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

KLHL29
NM_052920.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.37

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36227244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL29	NM_052920.2 link	c.8G>A	p.Arg3Gln	missense_variant	Exon 3 of 14	ENST00000486442.6	NP_443152.1	Q96CT2-1
KLHL29	XM_006711929.4 link	c.8G>A	p.Arg3Gln	missense_variant	Exon 2 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.8G>A	p.Arg3Gln	missense_variant	Exon 3 of 14	5	NM_052920.2	ENSP00000420659.1		Q96CT2-1
KLHL29	ENST00000489446.1 link	n.89G>A		non_coding_transcript_exon_variant	Exon 2 of 4	1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000333

AC:

AN:

150264

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000722

AC:

101

AN:

1398300

Hom.:

Cov.:

AF XY:

0.0000725

AC XY:

AN XY:

689674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000843

Gnomad4 OTH exome

AF:

0.0000862

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000411

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8G>A (p.R3Q) alteration is located in exon 3 (coding exon 1) of the KLHL29 gene. This alteration results from a G to A substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a glutamine (Q). 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

0.46

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.37

MutPred

0.19

Loss of MoRF binding (P = 0.0408);

MVP

0.76

ClinPred

0.42

GERP RS

4.7

Varity_R

0.36

gMVP

0.44

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