Variant 14-49725687-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_172193.3(KLHDC1):c.485A>G(p.Glu162Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000203 in 1,478,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 43)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

KLHDC1
NM_172193.3 missense, splice_region

Scores

Splicing: ADA: 0.8677

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.94

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:

KLHDC1 (HGNC:):

KLHDC1 links:

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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/exons	MANE	Protein	UniProt
KLHDC1	NM_172193.3 linkuse as main transcript	c.485A>G	p.Glu162Gly	missense_variant, splice_region_variant	6/13	ENST00000359332.7	NP_751943.1	Q8N7A1
KLHDC1	XM_011536422.3 linkuse as main transcript	c.485A>G	p.Glu162Gly	missense_variant, splice_region_variant	6/13		XP_011534724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC1	ENST00000359332.7 linkuse as main transcript	c.485A>G	p.Glu162Gly	missense_variant, splice_region_variant	6/13	1	NM_172193.3	ENSP00000352282.2		Q8N7A1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000443

AC:

AN:

225606

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122408

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000935

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1326218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665572

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:

0.00000199

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Nov 08, 2024

The c.485A>G (p.E162G) alteration is located in exon 6 (coding exon 6) of the KLHDC1 gene. This alteration results from a A to G substitution at nucleotide position 485, causing the glutamic acid (E) at amino acid position 162 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

0.26

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0072

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.25

Sift

Benign

0.32

T;T

Sift4G

Benign

0.29

T;T

Polyphen

1.0

D;D

Vest4

0.54

MutPred

0.51

Gain of catalytic residue at D158 (P = 0.0022);.;

MVP

0.83

MPC

0.32

ClinPred

0.93

GERP RS

5.6

Varity_R

0.11

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.050

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