4-87178609-A-G

Position:

• chr4-87178609-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020803.5(KLHL8):​c.964T>C​(p.Cys322Arg) 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: 9.11

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL8	NM_020803.5	c.964T>C	p.Cys322Arg	missense_variant	5/10	ENST00000273963.10	NP_065854.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL8	ENST00000273963.10	c.964T>C	p.Cys322Arg	missense_variant	5/10	1	NM_020803.5	ENSP00000273963	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 18, 2023

The c.964T>C (p.C322R) alteration is located in exon 5 (coding exon 4) of the KLHL8 gene. This alteration results from a T to C substitution at nucleotide position 964, causing the cysteine (C) at amino acid position 322 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.3	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.91
MutPred		0.77		Gain of MoRF binding (P = 9e-04);.;.;Gain of MoRF binding (P = 9e-04);
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.83
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88099761;