dbSNP rs2303771: KLHDC4:p.Thr102Ile (chr16-87755258-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017566.4(KLHDC4):c.305C>T(p.Thr102Ile) variant causes a missense change. The variant allele was found at a frequency of 0.364 in 1,597,314 control chromosomes in the GnomAD database, including 109,493 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.37 ( 10758 hom., cov: 32)

Exomes 𝑓: 0.36 ( 98735 hom. )

Consequence

KLHDC4
NM_017566.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.37

Publications

46 publications found

Variant links:

Genes affected

KLHDC4 (HGNC:25272): (kelch domain containing 4)

KLHDC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.9858947E-4).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC4	NM_017566.4 link	c.305C>T	p.Thr102Ile	missense_variant	Exon 4 of 12	ENST00000270583.10	NP_060036.2	Q8TBB5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC4	ENST00000270583.10 link	c.305C>T	p.Thr102Ile	missense_variant	Exon 4 of 12	1	NM_017566.4	ENSP00000270583.4		Q8TBB5-1
KLHDC4	ENST00000567298.5 link	n.305C>T		non_coding_transcript_exon_variant	Exon 4 of 17	5		ENSP00000457570.1		Q8TBB5-1

Frequencies

GnomAD3 genomes

AF:

0.372

AC:

56498

AN:

151824

Hom.:

10751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.386

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.350

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.392

AC:

98365

AN:

250844

AF XY:

0.394

show subpopulations

Gnomad AFR exome

AF:

0.379

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.347

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.363

AC:

524358

AN:

1445372

Hom.:

98735

Cov.:

AF XY:

0.368

AC XY:

264715

AN XY:

719744

show subpopulations

African (AFR)

AF:

0.374

AC:

12382

AN:

33078

American (AMR)

AF:

0.476

AC:

21215

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7924

AN:

26018

East Asian (EAS)

AF:

0.365

AC:

14461

AN:

39592

South Asian (SAS)

AF:

0.530

AC:

45511

AN:

85914

European-Finnish (FIN)

AF:

0.364

AC:

19387

AN:

53236

Middle Eastern (MID)

AF:

0.327

AC:

1881

AN:

5746

European-Non Finnish (NFE)

AF:

0.346

AC:

379989

AN:

1097432

Other (OTH)

AF:

0.361

AC:

21608

AN:

59808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

14482

28963

43445

57926

72408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12236

24472

36708

48944

61180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.372

AC:

56539

AN:

151942

Hom.:

10758

Cov.:

AF XY:

0.377

AC XY:

28006

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.386

AC:

15980

AN:

41422

American (AMR)

AF:

0.425

AC:

6488

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1076

AN:

3466

East Asian (EAS)

AF:

0.365

AC:

1887

AN:

5166

South Asian (SAS)

AF:

0.531

AC:

2560

AN:

4820

European-Finnish (FIN)

AF:

0.356

AC:

3756

AN:

10546

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.350

AC:

23792

AN:

67950

Other (OTH)

AF:

0.337

AC:

710

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1817

3634

5450

7267

9084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.358

Hom.:

30854

Bravo

AF:

0.373

TwinsUK

AF:

0.356

AC:

1319

ALSPAC

AF:

0.354

AC:

1363

ESP6500AA

AF:

0.379

AC:

1665

ESP6500EA

AF:

0.352

AC:

3025

ExAC

AF:

0.392

AC:

47578

Asia WGS

AF:

0.415

AC:

1443

AN:

3478

EpiCase

AF:

0.338

EpiControl

AF:

0.335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.8

(source)

DANN

Benign

0.069

DEOGEN2

Benign

0.0023

.;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.50

T;T;T;T

MetaRNN

Benign

0.00030

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

.;N;N;.

PhyloP100

4.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

3.7

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;.

Polyphen

0.0010

B;B;B;.

Vest4

0.20

MPC

0.013

ClinPred

0.0079

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over