NM_152467.5:c.261C>T

Variant names:

• chr17-41841889-C-T
• rs1529933
• NM_152467.5:c.261C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152467.5(KLHL10):​c.261C>T​(p.Pro87Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,613,950 control chromosomes in the GnomAD database, including 473,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P87P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.76 (44038 hom., cov: 32)
  • Exomes 𝑓: 0.76 (429024 hom.)
• Consequence: KLHL10 NM_152467.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.25
• Publications: 26 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-41841889-C-T is Benign according to our data. Variant chr17-41841889-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152467.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL10	NM_152467.5	MANE Select	c.261C>T	p.Pro87Pro	synonymous	Exon 2 of 5	NP_689680.2	A0A140VJM8
	KLHL10	NM_001329596.2		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001316525.1	B4DX37
	KLHL10	NM_001329595.1		c.261C>T	p.Pro87Pro	synonymous	Exon 4 of 7	NP_001316524.1	A0A140VJM8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL10	ENST00000293303.5	TSL:1 MANE Select	c.261C>T	p.Pro87Pro	synonymous	Exon 2 of 5	ENSP00000293303.4	Q6JEL2
	KLHL10	ENST00000859834.1		c.261C>T	p.Pro87Pro	synonymous	Exon 4 of 7	ENSP00000529893.1
	KLHL10	ENST00000913027.1		c.261C>T	p.Pro87Pro	synonymous	Exon 4 of 7	ENSP00000583086.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115318 AN: 151970 Hom.: 44007 Cov.: 32

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.782

GnomAD2 exomes AF: 0.783 AC: 195508 AN: 249562 AF XY: 0.784

Gnomad AFR exome AF: 0.728

Gnomad AMR exome AF: 0.885

Gnomad ASJ exome AF: 0.875

Gnomad EAS exome AF: 0.820

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.793

GnomAD4 exome AF: 0.765 AC: 1117761 AN: 1461862 Hom.: 429024 Cov.: 58 AF XY: 0.767 AC XY: 557950 AN XY: 727238

African (AFR) AF: 0.720 AC: 24107 AN: 33478

American (AMR) AF: 0.880 AC: 39373 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 22748 AN: 26136

East Asian (EAS) AF: 0.839 AC: 33326 AN: 39700

South Asian (SAS) AF: 0.828 AC: 71425 AN: 86258

European-Finnish (FIN) AF: 0.653 AC: 34877 AN: 53418

Middle Eastern (MID) AF: 0.824 AC: 4750 AN: 5768

European-Non Finnish (NFE) AF: 0.756 AC: 840544 AN: 1111984

Other (OTH) AF: 0.772 AC: 46611 AN: 60396

GnomAD4 genome AF: 0.759 AC: 115394 AN: 152088 Hom.: 44038 Cov.: 32 AF XY: 0.756 AC XY: 56240 AN XY: 74350

African (AFR) AF: 0.727 AC: 30154 AN: 41482

American (AMR) AF: 0.845 AC: 12903 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3019 AN: 3472

East Asian (EAS) AF: 0.824 AC: 4257 AN: 5168

South Asian (SAS) AF: 0.827 AC: 3990 AN: 4824

European-Finnish (FIN) AF: 0.629 AC: 6644 AN: 10570

Middle Eastern (MID) AF: 0.808 AC: 236 AN: 292

European-Non Finnish (NFE) AF: 0.762 AC: 51788 AN: 67994

Other (OTH) AF: 0.782 AC: 1650 AN: 2110

Alfa AF: 0.764 Hom.: 32915

Bravo AF: 0.774

Asia WGS AF: 0.818 AC: 2846 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Spermatogenic failure 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1529933; hg19: chr17-39998141; COSMIC: COSV108095032;