4-87170551-T-A

Position:

• chr4-87170551-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020803.5(KLHL8):​c.1273A>T​(p.Thr425Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL8 NM_020803.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19208115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL8	NM_020803.5	c.1273A>T	p.Thr425Ser	missense_variant	7/10	ENST00000273963.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL8	ENST00000273963.10	c.1273A>T	p.Thr425Ser	missense_variant	7/10	1	NM_020803.5	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

Jun 22, 2023

The c.1273A>T (p.T425S) alteration is located in exon 7 (coding exon 6) of the KLHL8 gene. This alteration results from a A to T substitution at nucleotide position 1273, causing the threonine (T) at amino acid position 425 to be replaced by a serine (S). 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	0.081
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.17	T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.76	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.0	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.015	B;.;B;B
Vest4		0.16
MutPred		0.37		Gain of glycosylation at T425 (P = 0.1009);.;.;Gain of glycosylation at T425 (P = 0.1009);
MVP		0.71
MPC		0.40
ClinPred		0.79	D
GERP RS		5.5
Varity_R		0.13
gMVP		0.077

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: chr4-88091703;