Variant 14-49693277-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_172193.3(KLHDC1):c.83G>T(p.Trp28Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,549,656 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

KLHDC1
NM_172193.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.24

Variant links:

Genes affected

KLHDC1 (HGNC:19836): (kelch domain containing 1) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Is active in Cul5-RING ubiquitin ligase complex and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC1 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=0.34009945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC1	NM_172193.3 linkuse as main transcript	c.83G>T	p.Trp28Leu	missense_variant	1/13	ENST00000359332.7	NP_751943.1
KLHDC1	XM_011536422.3 linkuse as main transcript	c.83G>T	p.Trp28Leu	missense_variant	1/13		XP_011534724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC1	ENST00000359332.7 linkuse as main transcript	c.83G>T	p.Trp28Leu	missense_variant	1/13	1	NM_172193.3	ENSP00000352282	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

184204

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

102042

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000851

Gnomad FIN exome

AF:

0.0000521

Gnomad NFE exome

AF:

0.000191

Gnomad OTH exome

AF:

0.000487

GnomAD4 exome

AF:

0.000132

AC:

185

AN:

1397530

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

693058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000348

Gnomad4 AMR exome

AF:

0.000243

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000306

Gnomad4 SAS exome

AF:

0.0000376

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.0000696

GnomAD4 genome

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000106

ExAC

AF:

0.000141

AC:

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

Jul 26, 2021

The c.83G>T (p.W28L) alteration is located in exon 1 (coding exon 1) of the KLHDC1 gene. This alteration results from a G to T substitution at nucleotide position 83, causing the tryptophan (W) at amino acid position 28 to be replaced by a leucine (L). 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

0.93

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-9.3

D;D;N

REVEL

Benign

0.24

Sift

Uncertain

0.0050

D;D;T

Sift4G

Uncertain

0.010

D;D;T

Polyphen

0.17

B;.;.

Vest4

0.68

MutPred

0.68

Gain of catalytic residue at N23 (P = 0);Gain of catalytic residue at N23 (P = 0);Gain of catalytic residue at N23 (P = 0);

MVP

0.74

MPC

0.21

ClinPred

0.25

GERP RS

4.6

Varity_R

0.88

gMVP

0.71

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