3-49173131-C-T

Position:

• chr3-49173131-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173546.3(KLHDC8B):​c.362C>T​(p.Ala121Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3143856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC8B	NM_173546.3	c.362C>T	p.Ala121Val	missense_variant	2/6	ENST00000332780.4	NP_775817.1
KLHDC8B	XM_006713015.4	c.362C>T	p.Ala121Val	missense_variant	2/6		XP_006713078.1
KLHDC8B	XM_006713016.4	c.362C>T	p.Ala121Val	missense_variant	2/6		XP_006713079.1
KLHDC8B	XM_005264938.4	c.362C>T	p.Ala121Val	missense_variant	2/6		XP_005264995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC8B	ENST00000332780.4	c.362C>T	p.Ala121Val	missense_variant	2/6	1	NM_173546.3	ENSP00000327468.2
KLHDC8B	ENST00000476495.2	n.419C>T		non_coding_transcript_exon_variant	1/3	2
KLHDC8B	ENST00000459846.6	n.230+330C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419300 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702468

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 07, 2024

The c.362C>T (p.A121V) 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 362, causing the alanine (A) at amino acid position 121 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	0.22
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		0.094	B
Vest4		0.28
MutPred		0.52		Gain of glycosylation at T122 (P = 0.032);
MVP		0.80
MPC		0.46
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49210564;