17-41841990-T-C

Variant names:

• chr17-41841990-T-C
• NM_152467.5:c.362T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152467.5(KLHL10):​c.362T>C​(p.Ile121Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. I121V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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]

KLHL10 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 11

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.362T>C	p.Ile121Thr	missense_variant	Exon 2 of 5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.362T>C	p.Ile121Thr	missense_variant	Exon 4 of 7		NP_001316524.1
KLHL10	NM_001329596.2	c.98T>C	p.Ile33Thr	missense_variant	Exon 2 of 5		NP_001316525.1
KLHL10	XM_047435897.1	c.362T>C	p.Ile121Thr	missense_variant	Exon 3 of 6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5	c.362T>C	p.Ile121Thr	missense_variant	Exon 2 of 5	1	NM_152467.5	ENSP00000293303.4
KLHL10	ENST00000438813.1	c.344T>C	p.Ile115Thr	missense_variant	Exon 2 of 2	4		ENSP00000416221.1
KLHL10	ENST00000448203.2	c.362T>C	p.Ile121Thr	missense_variant	Exon 4 of 4	4		ENSP00000391983.2
KLHL10	ENST00000485613.1	n.408T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362T>C (p.I121T) alteration is located in exon 2 (coding exon 2) of the KLHL10 gene. This alteration results from a T to C substitution at nucleotide position 362, causing the isoleucine (I) at amino acid position 121 to be replaced by a threonine (T). 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	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.80	.;P;.
Vest4		0.86
MutPred		0.77		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);.;
MVP		0.82
MPC		1.4
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.79
Mutation Taster		=47/53	disease causing

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

hg19: chr17-39998242;