17-41837496-T-C

Variant names:

• chr17-41837496-T-C
• rs4796714
• NM_001329595.1:c.-99T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001329595.1(KLHL10):​c.-99T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 978,254 control chromosomes in the GnomAD database, including 283,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (44938 hom., cov: 33)
  • Exomes 𝑓: 0.76 (238276 hom.)
• Consequence: KLHL10 NM_001329595.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.505
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-41837496-T-C is Benign according to our data. Variant chr17-41837496-T-C is described in ClinVar as [Benign]. Clinvar id is 1263658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_001329595.1	c.-99T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7		NP_001316524.1
KLHL10	XM_047435897.1	c.-99T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6		XP_047291853.1
KLHL10	NM_001329595.1	c.-99T>C		5_prime_UTR_variant	Exon 2 of 7		NP_001316524.1
KLHL10	XM_047435897.1	c.-99T>C		5_prime_UTR_variant	Exon 1 of 6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000448203.2	c.-99T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	4		ENSP00000391983.2
KLHL10	ENST00000448203.2	c.-99T>C		5_prime_UTR_variant	Exon 2 of 4	4		ENSP00000391983.2

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116486 AN: 152030 Hom.: 44902 Cov.: 33

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.757 AC: 625483 AN: 826106 Hom.: 238276 Cov.: 15 AF XY: 0.757 AC XY: 290491 AN XY: 383592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.744 AC: 11897 AN: 15986

American (AMR) AF: 0.853 AC: 3393 AN: 3976

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 4804 AN: 5492

East Asian (EAS) AF: 0.829 AC: 4266 AN: 5146

South Asian (SAS) AF: 0.822 AC: 15338 AN: 18670

European-Finnish (FIN) AF: 0.648 AC: 599 AN: 924

Middle Eastern (MID) AF: 0.816 AC: 1333 AN: 1634

European-Non Finnish (NFE) AF: 0.753 AC: 562584 AN: 746832

Other (OTH) AF: 0.775 AC: 21269 AN: 27446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.766 AC: 116570 AN: 152148 Hom.: 44938 Cov.: 33 AF XY: 0.764 AC XY: 56822 AN XY: 74376

African (AFR) AF: 0.752 AC: 31240 AN: 41518

American (AMR) AF: 0.848 AC: 12965 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 3021 AN: 3470

East Asian (EAS) AF: 0.827 AC: 4273 AN: 5168

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

European-Finnish (FIN) AF: 0.627 AC: 6640 AN: 10582

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51795 AN: 67976

Other (OTH) AF: 0.784 AC: 1655 AN: 2112

Alfa AF: 0.775 Hom.: 7439

Bravo AF: 0.782

Asia WGS AF: 0.827 AC: 2876 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		-0.51
PromoterAI		0.011	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4796714; hg19: chr17-39993748;