4-87176845-G-A

Position:

• chr4-87176845-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020803.5(KLHL8):​c.1120C>T​(p.His374Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL8 NM_020803.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.79

Genes affected

KLHL8 (HGNC:18644): (kelch like family member 8) Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process. Located in nucleoplasm. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL8	NM_020803.5	c.1120C>T	p.His374Tyr	missense_variant	6/10	ENST00000273963.10	NP_065854.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL8	ENST00000273963.10	c.1120C>T	p.His374Tyr	missense_variant	6/10	1	NM_020803.5	ENSP00000273963	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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

Jul 12, 2022

The c.1120C>T (p.H374Y) alteration is located in exon 6 (coding exon 5) of the KLHL8 gene. This alteration results from a C to T substitution at nucleotide position 1120, causing the histidine (H) at amino acid position 374 to be replaced by a tyrosine (Y). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;.
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.070	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;T;D;D
Sift4G	Uncertain	0.036	D;T;D;D
Polyphen		1.0	D;.;B;D
Vest4		0.75
MutPred		0.53		Gain of glycosylation at Y369 (P = 0.0083);.;.;Gain of glycosylation at Y369 (P = 0.0083);
MVP		0.80
MPC		1.4
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1188291814; hg19: chr4-88097997;