chr3-49172938-C-T

Position:

chr3-49172938-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_173546.3(KLHDC8B):c.169C>T(p.His57Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H57H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

KLHDC8B
NM_173546.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

KLHDC8B (HGNC:28557): (kelch domain containing 8B) This gene encodes a protein which forms a distinct beta-propeller protein structure of kelch domains allowing for protein-protein interactions. Mutations in this gene have been associated with Hodgkin lymphoma. [provided by RefSeq, Sep 2010]

KLHDC8B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15076467).

BS2

High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KLHDC8B	NM_173546.3 linkuse as main transcript	c.169C>T	p.His57Tyr	missense_variant	2/6	ENST00000332780.4
KLHDC8B	XM_006713015.4 linkuse as main transcript	c.169C>T	p.His57Tyr	missense_variant	2/6
KLHDC8B	XM_006713016.4 linkuse as main transcript	c.169C>T	p.His57Tyr	missense_variant	2/6
KLHDC8B	XM_005264938.4 linkuse as main transcript	c.169C>T	p.His57Tyr	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KLHDC8B	ENST00000332780.4 linkuse as main transcript	c.169C>T	p.His57Tyr	missense_variant	2/6	1	NM_173546.3	P1
KLHDC8B	ENST00000476495.2 linkuse as main transcript	n.226C>T		non_coding_transcript_exon_variant	1/3	2
KLHDC8B	ENST00000459846.6 linkuse as main transcript	n.230+137C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000192

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

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

251100

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.169C>T (p.H57Y) alteration is located in exon 2 (coding exon 1) of the KLHDC8B gene. This alteration results from a C to T substitution at nucleotide position 169, causing the histidine (H) at amino acid position 57 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 57 of the KLHDC8B protein (p.His57Tyr). This variant is present in population databases (rs750808403, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KLHDC8B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2509134). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.019

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.92

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Uncertain

0.028

Sift4G

Benign

0.078

Polyphen

0.91

Vest4

0.18

MVP

0.67

MPC

0.81

ClinPred

0.32

GERP RS

5.3

Varity_R

0.29

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over