Genetic Variant KHDC3L:p.Ala201Gly (chr6-73363808-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001017361.3(KHDC3L):c.602C>G(p.Ala201Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 1,612,242 control chromosomes in the GnomAD database, including 242,850 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 Benign (★).

Frequency

Genomes: 𝑓 0.49 ( 18693 hom., cov: 31)

Exomes 𝑓: 0.55 ( 224157 hom. )

Consequence

KHDC3L
NM_001017361.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.137

Publications

35 publications found

Variant links:

Genes affected

KHDC3L (HGNC:33699): (KH domain containing 3 like, subcortical maternal complex member) The protein encoded by this gene belongs to the KHDC1 family, members of which contain an atypical KH domain that may not bind RNA like canonical KH domains. This gene is specifically expressed in the oocytes, and recent studies suggest that it may function as a regulator of genomic imprinting in the oocyte. Mutations in this gene are associated with recurrent biparental complete hydatidiform mole. [provided by RefSeq, Dec 2011]

KHDC3L Gene-Disease associations (from GenCC):

hydatidiform mole, recurrent, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
complete hydatidiform mole
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KHDC3L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.251118E-5).

BP6

Variant 6-73363808-C-G is Benign according to our data. Variant chr6-73363808-C-G is described in ClinVar as [Benign]. Clinvar id is 997714.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC3L	NM_001017361.3 link	c.602C>G	p.Ala201Gly	missense_variant	Exon 3 of 3	ENST00000370367.4	NP_001017361.1	Q587J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHDC3L	ENST00000370367.4 link	c.602C>G	p.Ala201Gly	missense_variant	Exon 3 of 3	1	NM_001017361.3	ENSP00000359392.3		Q587J8

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74000

AN:

151790

Hom.:

18694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.470

Gnomad EAS

AF:

0.537

Gnomad SAS

AF:

0.603

Gnomad FIN

AF:

0.541

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.518

AC:

128674

AN:

248470

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.350

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.463

Gnomad EAS exome

AF:

0.541

Gnomad FIN exome

AF:

0.539

Gnomad NFE exome

AF:

0.554

Gnomad OTH exome

AF:

0.511

GnomAD4 exome

AF:

0.551

AC:

805333

AN:

1460332

Hom.:

224157

Cov.:

AF XY:

0.554

AC XY:

402248

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.350

AC:

11726

AN:

33472

American (AMR)

AF:

0.413

AC:

18455

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12036

AN:

26136

East Asian (EAS)

AF:

0.523

AC:

20772

AN:

39696

South Asian (SAS)

AF:

0.590

AC:

50859

AN:

86258

European-Finnish (FIN)

AF:

0.530

AC:

27554

AN:

51988

Middle Eastern (MID)

AF:

0.550

AC:

3173

AN:

5764

European-Non Finnish (NFE)

AF:

0.565

AC:

628718

AN:

1111926

Other (OTH)

AF:

0.531

AC:

32040

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

21993

43986

65979

87972

109965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.487

AC:

74026

AN:

151910

Hom.:

18693

Cov.:

AF XY:

0.491

AC XY:

36470

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.354

AC:

14670

AN:

41452

American (AMR)

AF:

0.465

AC:

7097

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

1632

AN:

3470

East Asian (EAS)

AF:

0.536

AC:

2740

AN:

5112

South Asian (SAS)

AF:

0.603

AC:

2902

AN:

4816

European-Finnish (FIN)

AF:

0.541

AC:

5719

AN:

10566

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.555

AC:

37703

AN:

67918

Other (OTH)

AF:

0.504

AC:

1063

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1879

3758

5636

7515

9394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.526

Hom.:

14797

Bravo

AF:

0.472

TwinsUK

AF:

0.569

AC:

2109

ALSPAC

AF:

0.582

AC:

2242

ESP6500AA

AF:

0.368

AC:

1620

ESP6500EA

AF:

0.546

AC:

4696

ExAC

AF:

0.516

AC:

62656

Asia WGS

AF:

0.531

AC:

1853

AN:

3478

EpiCase

AF:

0.554

EpiControl

AF:

0.551

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hydatidiform mole

Benign:1

Feb 22, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0074

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.43

MetaRNN

Benign

0.000043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.14

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.27

REVEL

Benign

0.14

Sift

Benign

0.046

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.042

MPC

1.0

ClinPred

0.013

GERP RS

-0.56

Varity_R

0.066

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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chr6-73363808-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over