Genetic Variant NM_001365790.2:c.2338G>A (chr14-20428905-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001365790.2(KLHL33):c.2338G>A(p.Ala780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 1,551,436 control chromosomes in the GnomAD database, including 272,074 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 0.62 ( 29766 hom., cov: 34)

Exomes 𝑓: 0.59 ( 242308 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.877

Publications

27 publications found

Variant links:

Genes affected

KLHL33 (HGNC:31952): (kelch like family member 33)

KLHL33 links:

ENSG00000291038 (HGNC:):

ENSG00000291038 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=1.5052747E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL33	NM_001365790.2 link	c.2338G>A	p.Ala780Thr	missense_variant	Exon 5 of 5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3 link	c.1546G>A	p.Ala516Thr	missense_variant	Exon 4 of 4		NP_001103467.2	A6NCF5B2RUZ8
KLHL33	XM_011536450.3 link	c.2338G>A	p.Ala780Thr	missense_variant	Exon 5 of 5		XP_011534752.1	A0A1B0GUB7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3 link	c.2338G>A	p.Ala780Thr	missense_variant	Exon 5 of 5	5	NM_001365790.2	ENSP00000490040.1		A0A1B0GUB7

Frequencies

GnomAD3 genomes

AF:

0.622

AC:

94485

AN:

152020

Hom.:

29715

Cov.:

show subpopulations

Gnomad AFR

AF:

0.721

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.579

Gnomad EAS

AF:

0.602

Gnomad SAS

AF:

0.686

Gnomad FIN

AF:

0.617

Gnomad MID

AF:

0.666

Gnomad NFE

AF:

0.575

Gnomad OTH

AF:

0.644

GnomAD2 exomes

AF:

0.591

AC:

92430

AN:

156406

AF XY:

0.599

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.479

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.589

Gnomad FIN exome

AF:

0.617

Gnomad NFE exome

AF:

0.581

Gnomad OTH exome

AF:

0.600

GnomAD4 exome

AF:

0.587

AC:

821111

AN:

1399298

Hom.:

242308

Cov.:

AF XY:

0.589

AC XY:

406780

AN XY:

690162

show subpopulations

African (AFR)

AF:

0.724

AC:

22885

AN:

31598

American (AMR)

AF:

0.493

AC:

17585

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

15045

AN:

25180

East Asian (EAS)

AF:

0.585

AC:

20898

AN:

35736

South Asian (SAS)

AF:

0.672

AC:

53281

AN:

79232

European-Finnish (FIN)

AF:

0.607

AC:

29902

AN:

49274

Middle Eastern (MID)

AF:

0.663

AC:

3777

AN:

5698

European-Non Finnish (NFE)

AF:

0.577

AC:

622724

AN:

1078878

Other (OTH)

AF:

0.604

AC:

35014

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19188

38375

57563

76750

95938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17514

35028

52542

70056

87570

<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:

0.622

AC:

94597

AN:

152138

Hom.:

29766

Cov.:

AF XY:

0.626

AC XY:

46523

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.722

AC:

29963

AN:

41508

American (AMR)

AF:

0.554

AC:

8462

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

2009

AN:

3470

East Asian (EAS)

AF:

0.601

AC:

3112

AN:

5174

South Asian (SAS)

AF:

0.686

AC:

3314

AN:

4828

European-Finnish (FIN)

AF:

0.617

AC:

6531

AN:

10592

Middle Eastern (MID)

AF:

0.664

AC:

194

AN:

292

European-Non Finnish (NFE)

AF:

0.575

AC:

39063

AN:

67962

Other (OTH)

AF:

0.645

AC:

1362

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1894

3788

5683

7577

9471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

784

1568

2352

3136

3920

<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:

0.588

Hom.:

61000

Bravo

AF:

0.619

TwinsUK

AF:

0.593

AC:

2197

ALSPAC

AF:

0.581

AC:

2241

ESP6500AA

AF:

0.715

AC:

989

ESP6500EA

AF:

0.577

AC:

1835

ExAC

AF:

0.608

AC:

14960

Asia WGS

AF:

0.624

AC:

2173

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.55

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0024

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.12

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

.;L

PhyloP100

-0.88

PrimateAI

Benign

0.35

PROVEAN

Benign

0.22

.;N

REVEL

Benign

0.055

Sift

Benign

1.0

.;T

Sift4G

Benign

0.98

.;T

Polyphen

0.0010

.;B

Vest4

0.018

ClinPred

0.00059

GERP RS

-1.8

Varity_R

0.032

gMVP

0.27

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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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