Variant 6-73242217-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000257765.10(KHDC1):c.133C>T(p.Arg45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,426 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

KHDC1
ENST00000257765.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.334

Variant links:

Genes affected

KHDC1 (HGNC:21366): (KH domain containing 1) Predicted to enable identical protein binding activity and poly(U) RNA binding activity. Predicted to be involved in activation of cysteine-type endopeptidase activity involved in apoptotic process. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

KHDC1 links:

LOC122539213 (HGNC:):

LOC122539213 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18163893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC1	NM_030568.5 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	3/4	ENST00000257765.10	NP_085045.3
LOC122539213	NR_173146.1 linkuse as main transcript	n.797C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDC1	ENST00000257765.10 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	3/4	1	NM_030568.5	ENSP00000257765	P2	Q4VXA5-2
KHDC1	ENST00000370384.7 linkuse as main transcript	c.352C>T	p.Arg118Cys	missense_variant	4/5	1		ENSP00000359411	A2	Q4VXA5-1
KHDC1	ENST00000433730.1 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	3/3	3		ENSP00000406966

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000177

AC:

AN:

248092

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134534

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000658

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000285

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000174

AC:

254

AN:

1461254

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000177

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000534

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

Mar 28, 2023

The c.133C>T (p.R45C) alteration is located in exon 3 (coding exon 2) of the KHDC1 gene. This alteration results from a C to T substitution at nucleotide position 133, causing the arginine (R) at amino acid position 45 to be replaced by a cysteine (C). 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

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.043

.;T;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.67

.;T;T;T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

.;N;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.3

D;D;.;.;D

REVEL

Benign

0.094

Sift

Benign

0.064

T;.;.;.;T

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

1.0

.;D;.;.;.

Vest4

0.35

MVP

0.21

MPC

0.054

ClinPred

0.27

GERP RS

0.85

Varity_R

0.49

gMVP

0.020

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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