rs116420871

Positions:

• chr17-41842275-A-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_152467.5(KLHL10):​c.647A>C​(p.Gln216Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,614,166 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:3
• Conservation: PhyloP100: 0.528

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 Benign. Variant got -15 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005472094).
• BP6: Variant 17-41842275-A-C is Benign according to our data. Variant chr17-41842275-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 40008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.647A>C	p.Gln216Pro	missense_variant	2/5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.647A>C	p.Gln216Pro	missense_variant	4/7		NP_001316524.1
KLHL10	NM_001329596.2	c.383A>C	p.Gln128Pro	missense_variant	2/5		NP_001316525.1
KLHL10	XM_047435897.1	c.647A>C	p.Gln216Pro	missense_variant	3/6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5	c.647A>C	p.Gln216Pro	missense_variant	2/5	1	NM_152467.5	ENSP00000293303.4

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152214 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000980 AC: 244 AN: 249080 Hom.: 3 AF XY: 0.000614 AC XY: 83 AN XY: 135234

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000371 AC: 543 AN: 1461834 Hom.: 6 Cov.: 35 AF XY: 0.000322 AC XY: 234 AN XY: 727226

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152332 Hom.: 6 Cov.: 31 AF XY: 0.00313 AC XY: 233 AN XY: 74488

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000643 Hom.: 1

Bravo AF: 0.00388

ESP6500AA AF: 0.00761 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00123 AC: 149

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 11 Pathogenic:1 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_152467.3:c.647A>C in the KLHL10 gene has an allele frequency of 0.013 in African subpopulation in the gnomAD database. This variant has been detected in four individual with oligozoospermia (PMID: 17047026). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP4. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.69
MVP		0.43
MPC		0.75
ClinPred		0.0045	T
GERP RS		2.1
Varity_R		0.42
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs116420871; hg19: chr17-39998527;