3-49172933-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173546.3(KLHDC8B):c.164C>T(p.Ala55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08918747).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHDC8B	NM_173546.3	c.164C>T	p.Ala55Val	missense_variant	2/6	ENST00000332780.4
KLHDC8B	XM_006713015.4	c.164C>T	p.Ala55Val	missense_variant	2/6
KLHDC8B	XM_006713016.4	c.164C>T	p.Ala55Val	missense_variant	2/6
KLHDC8B	XM_005264938.4	c.164C>T	p.Ala55Val	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC8B	ENST00000332780.4	c.164C>T	p.Ala55Val	missense_variant	2/6	1	NM_173546.3	P1
KLHDC8B	ENST00000476495.2	n.221C>T		non_coding_transcript_exon_variant	1/3	2
KLHDC8B	ENST00000459846.6	n.230+132C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251104 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135816

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000624 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.164C>T (p.A55V) 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 164, causing the alanine (A) at amino acid position 55 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.16	N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.014
Sift	Benign	0.12	T
Sift4G	Benign	0.99	T
Polyphen		0.016	B
Vest4		0.055
MutPred		0.36		Loss of disorder (P = 0.0926);
MVP		0.49
MPC		0.44
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.058
gMVP		0.28

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

Other links and lift over

dbSNP: rs775044801; hg19: chr3-49210366;