17-41842092-A-G

Position:

• chr17-41842092-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000293303.5(KLHL10):​c.464A>G​(p.Glu155Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E155K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL10 ENST00000293303.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

Genes affected

KLHL10 (HGNC:18829): (kelch like family member 10) The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL10. . Gene score misZ 2.7236 (greater than the threshold 3.09). Trascript score misZ 4.4991 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.464A>G	p.Glu155Gly	missense_variant	2/5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.464A>G	p.Glu155Gly	missense_variant	4/7		NP_001316524.1
KLHL10	NM_001329596.2	c.200A>G	p.Glu67Gly	missense_variant	2/5		NP_001316525.1
KLHL10	XM_047435897.1	c.464A>G	p.Glu155Gly	missense_variant	3/6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5	c.464A>G	p.Glu155Gly	missense_variant	2/5	1	NM_152467.5	ENSP00000293303	P1
KLHL10	ENST00000438813.1	c.446A>G	p.Glu149Gly	missense_variant	2/2	4		ENSP00000416221
KLHL10	ENST00000485613.1	n.510A>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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

Feb 22, 2023

The c.464A>G (p.E155G) alteration is located in exon 2 (coding exon 2) of the KLHL10 gene. This alteration results from a A to G substitution at nucleotide position 464, causing the glutamic acid (E) at amino acid position 155 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.27
Sift	Benign	0.28	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.028	B;.
Vest4		0.18
MutPred		0.54		Loss of ubiquitination at K159 (P = 0.0653);.;
MVP		0.65
MPC		0.73
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr17-39998344;