3-49172851-C-A

Variant names:

• chr3-49172851-C-A
• rs781302926
• NM_173546.3:c.82C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_173546.3(KLHDC8B):​c.82C>A​(p.His28Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.000010 (0 hom.)
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.322

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.096295744).
• BS2: High AC in GnomAdExome4 at 15 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 rank	MANE	Protein	UniProt
KLHDC8B	NM_173546.3	c.82C>A	p.His28Asn	missense_variant	Exon 2 of 6	ENST00000332780.4	NP_775817.1
KLHDC8B	XM_006713015.4	c.82C>A	p.His28Asn	missense_variant	Exon 2 of 6		XP_006713078.1
KLHDC8B	XM_006713016.4	c.82C>A	p.His28Asn	missense_variant	Exon 2 of 6		XP_006713079.1
KLHDC8B	XM_005264938.4	c.82C>A	p.His28Asn	missense_variant	Exon 2 of 6		XP_005264995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC8B	ENST00000332780.4	c.82C>A	p.His28Asn	missense_variant	Exon 2 of 6	1	NM_173546.3	ENSP00000327468.2
KLHDC8B	ENST00000476495.2	n.139C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
KLHDC8B	ENST00000459846.6	n.230+50C>A		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250390 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135432

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727202

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 28 of the KLHDC8B protein (p.His28Asn). This variant is present in population databases (rs781302926, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KLHDC8B-related conditions. 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	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.017
Sift	Benign	0.28	T
Sift4G	Benign	0.39	T
Polyphen		0.13	B
Vest4		0.13
MutPred		0.35		Gain of glycosylation at Y23 (P = 0.032);
MVP		0.69
MPC		0.56
ClinPred		0.064	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.60

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: rs781302926; hg19: chr3-49210284;