chr17-41842275-A-C

Position:

• chr17-41842275-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. 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 -16 ACMG points.

• 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;