Genetic Variant KLHDC9:p.Ser171Arg (chr1-161099046-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_152366.5(KLHDC9):c.511A>C(p.Ser171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,595,180 control chromosomes in the GnomAD database, including 67,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.24 ( 5124 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62312 hom. )

Consequence

KLHDC9
NM_152366.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.38

Publications

40 publications found

Variant links:

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC9 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=0.0029716194).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC9	NM_152366.5 link	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4	ENST00000368011.9	NP_689579.3	Q8NEP7-1
KLHDC9	NM_001007255.3 link	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4		NP_001007256.1	Q8NEP7-2
KLHDC9	NR_033385.2 link	n.425A>C		non_coding_transcript_exon_variant	Exon 2 of 5
KLHDC9	NR_033386.2 link	n.425A>C		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC9	ENST00000368011.9 link	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4	1	NM_152366.5	ENSP00000356990.4		Q8NEP7-1

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36738

AN:

152016

Hom.:

5126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0980

Gnomad AMI

AF:

0.373

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.245

GnomAD2 exomes

AF:

0.275

AC:

62139

AN:

225880

AF XY:

0.273

show subpopulations

Gnomad AFR exome

AF:

0.0881

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.347

Gnomad FIN exome

AF:

0.312

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.289

GnomAD4 exome

AF:

0.291

AC:

420082

AN:

1443046

Hom.:

62312

Cov.:

AF XY:

0.289

AC XY:

207233

AN XY:

718026

show subpopulations

African (AFR)

AF:

0.0858

AC:

2861

AN:

33364

American (AMR)

AF:

0.309

AC:

13684

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

7257

AN:

26074

East Asian (EAS)

AF:

0.388

AC:

15278

AN:

39420

South Asian (SAS)

AF:

0.206

AC:

17675

AN:

85718

European-Finnish (FIN)

AF:

0.305

AC:

11622

AN:

38154

Middle Eastern (MID)

AF:

0.241

AC:

1388

AN:

5760

European-Non Finnish (NFE)

AF:

0.301

AC:

333661

AN:

1110062

Other (OTH)

AF:

0.277

AC:

16656

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

17330

34660

51991

69321

86651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10982

21964

32946

43928

54910

<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:

0.242

AC:

36750

AN:

152134

Hom.:

5124

Cov.:

AF XY:

0.243

AC XY:

18053

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0982

AC:

4080

AN:

41536

American (AMR)

AF:

0.282

AC:

4313

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

971

AN:

3470

East Asian (EAS)

AF:

0.365

AC:

1888

AN:

5174

South Asian (SAS)

AF:

0.203

AC:

977

AN:

4820

European-Finnish (FIN)

AF:

0.321

AC:

3395

AN:

10572

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20201

AN:

67966

Other (OTH)

AF:

0.247

AC:

522

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1394

2789

4183

5578

6972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.280

Hom.:

21183

Bravo

AF:

0.236

TwinsUK

AF:

0.292

AC:

1081

ALSPAC

AF:

0.284

AC:

1094

ESP6500AA

AF:

0.0927

AC:

407

ESP6500EA

AF:

0.282

AC:

2416

ExAC

AF:

0.262

AC:

31660

Asia WGS

AF:

0.258

AC:

897

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.3

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.0047

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;N

PhyloP100

-1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.93

N;N

REVEL

Benign

0.052

Sift

Benign

0.52

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0

B;B

Vest4

0.17

MutPred

0.22

Gain of MoRF binding (P = 0.0164);Gain of MoRF binding (P = 0.0164);

MPC

0.34

ClinPred

0.0034

GERP RS

-7.1

Varity_R

0.042

gMVP

0.51

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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