Variant 6-73241684-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030568.5(KHDC1):c.340G>A(p.Asp114Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

KHDC1
NM_030568.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0860

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:

ENSG00000243501 (HGNC:):

ENSG00000243501 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017130613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC1	NM_030568.5 linkuse as main transcript	c.340G>A	p.Asp114Asn	missense_variant	4/4	ENST00000257765.10	NP_085045.3	Q4VXA5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KHDC1	ENST00000257765.10 linkuse as main transcript	c.340G>A	p.Asp114Asn	missense_variant	4/4	1	NM_030568.5	ENSP00000257765.5	Q4VXA5-2
KHDC1	ENST00000370384.7 linkuse as main transcript	c.559G>A	p.Asp187Asn	missense_variant	5/5	1		ENSP00000359411.3	Q4VXA5-1
ENSG00000243501	ENST00000423730.3 linkuse as main transcript	n.295+371G>A		intron_variant		5		ENSP00000457270.2	F5H697

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.00137

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000473

AC:

118

AN:

249470

Hom.:

AF XY:

0.000429

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000145

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:

0.000928

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00117

AC:

1712

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

807

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00149

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152264

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000816

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000743

AC:

ESP6500EA

AF:

0.00131

AC:

ExAC

AF:

0.000422

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000948

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

Sep 27, 2021

The c.340G>A (p.D114N) alteration is located in exon 4 (coding exon 3) of the KHDC1 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the aspartic acid (D) at amino acid position 114 to be replaced by an asparagine (N). 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

0.10

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.7

DANN

Benign

0.95

DEOGEN2

Benign

0.0078

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.16

.;T;T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;N;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Benign

0.0040

Sift

Benign

0.33

T;.;.;.

Sift4G

Benign

0.39

T;T;T;T

Polyphen

0.037

.;B;.;.

Vest4

0.13

MVP

0.014

MPC

0.043

ClinPred

0.0072

GERP RS

-2.6

Varity_R

0.28

gMVP

0.0062

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