NM_173546.3:c.169C>A

Variant names:

• chr3-49172938-C-A
• rs750808403
• NM_173546.3:c.169C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173546.3(KLHDC8B):​c.169C>A​(p.His57Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H57Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• classic Hodgkin lymphoma

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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=0.11012253).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173546.3. 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
	KLHDC8B	NM_173546.3	MANE Select	c.169C>A	p.His57Asn	missense	Exon 2 of 6	NP_775817.1	Q8IXV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8B	ENST00000332780.4	TSL:1 MANE Select	c.169C>A	p.His57Asn	missense	Exon 2 of 6	ENSP00000327468.2	Q8IXV7
	KLHDC8B	ENST00000948547.1		c.169C>A	p.His57Asn	missense	Exon 2 of 6	ENSP00000618606.1
	KLHDC8B	ENST00000948549.1		c.169C>A	p.His57Asn	missense	Exon 2 of 6	ENSP00000618608.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.74	N
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.11
Sift	Benign	0.53	T
Sift4G	Benign	0.92	T
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.41		Loss of glycosylation at S56 (P = 0.1002)
MVP		0.38
MPC		0.57
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.42
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs750808403; hg19: chr3-49210371;