Genetic Variant KLHDC7B:p.Arg774His (chr22-50548564-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138433.5(KLHDC7B):c.2321G>A(p.Arg774His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,548,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R774L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KLHDC7B
NM_138433.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.126

Publications

1 publications found

Variant links:

Genes affected

KLHDC7B (HGNC:25145): (kelch domain containing 7B)

KLHDC7B links:

KLHDC7B-DT (HGNC:53791): (KLHDC7B divergent transcript)

KLHDC7B-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08367035).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC7B	NM_138433.5	MANE Select	c.2321G>A	p.Arg774His	missense	Exon 1 of 1	NP_612442.3	A0A3B3ISF6
	KLHDC7B-DT	NR_199716.1		n.52+332C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHDC7B	ENST00000648057.3	MANE Select	c.2321G>A	p.Arg774His	missense	Exon 1 of 1	ENSP00000497256.1	A0A3B3ISF6
KLHDC7B-DT	ENST00000796178.1		n.99+332C>T		intron	N/A
KLHDC7B-DT	ENST00000796179.1		n.30+260C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

144096

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396558

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31796

American (AMR)

AF:

0.00

AC:

AN:

35718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

36018

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079394

Other (OTH)

AF:

0.00

AC:

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41342

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000103

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0053

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.25

PhyloP100

-0.13

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Benign

0.095

Sift4G

Uncertain

0.025

Polyphen

0.029

Vest4

0.082

MutPred

0.22

Loss of MoRF binding (P = 0.0457)

MVP

0.71

ClinPred

0.090

GERP RS

1.4

Varity_R

0.030

gMVP

0.17

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over