chr17-41841989-A-C

Variant names:

• chr17-41841989-A-C
• rs1230073631
• NM_152467.5:c.361A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_152467.5(KLHL10):​c.361A>C​(p.Ile121Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I121T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.283628).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.361A>C	p.Ile121Leu	missense_variant	Exon 2 of 5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.361A>C	p.Ile121Leu	missense_variant	Exon 4 of 7		NP_001316524.1
KLHL10	NM_001329596.2	c.97A>C	p.Ile33Leu	missense_variant	Exon 2 of 5		NP_001316525.1
KLHL10	XM_047435897.1	c.361A>C	p.Ile121Leu	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.361A>C	p.Ile121Leu	missense_variant	Exon 2 of 5	1	NM_152467.5	ENSP00000293303.4
KLHL10	ENST00000438813.1	c.343A>C	p.Ile115Leu	missense_variant	Exon 2 of 2	4		ENSP00000416221.1
KLHL10	ENST00000448203.2	c.361A>C	p.Ile121Leu	missense_variant	Exon 4 of 4	4		ENSP00000391983.2
KLHL10	ENST00000485613.1	n.407A>C		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 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: 0.00000450 AC: 5 AN: 1112012

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.45	.;N;.
PhyloP100		2.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.23
Sift	Benign	0.034	.;D;T
Sift4G	Uncertain	0.044	D;T;T
Polyphen		0.27	.;B;.
Vest4		0.27
MutPred		0.65		Loss of catalytic residue at I121 (P = 0.1022);Loss of catalytic residue at I121 (P = 0.1022);.;
MVP		0.40
MPC		0.69
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.58
Mutation Taster		=81/19	polymorphism

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

dbSNP: rs1230073631; hg19: chr17-39998241;