17-41838005-G-A

Position:

• chr17-41838005-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_152467.5(KLHL10):​c.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.10851166).
• BP6: Variant 17-41838005-G-A is Benign according to our data. Variant chr17-41838005-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2534219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.73G>A	p.Ala25Thr	missense_variant	1/5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.73G>A	p.Ala25Thr	missense_variant	3/7		NP_001316524.1
KLHL10	XM_047435897.1	c.73G>A	p.Ala25Thr	missense_variant	2/6		XP_047291853.1
KLHL10	NM_001329596.2	c.-130G>A		5_prime_UTR_variant	1/5		NP_001316525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5	c.73G>A	p.Ala25Thr	missense_variant	1/5	1	NM_152467.5	ENSP00000293303.4
KLHL10	ENST00000438813.1	c.73G>A	p.Ala25Thr	missense_variant	1/2	4		ENSP00000416221.1
KLHL10	ENST00000448203.2	c.73G>A	p.Ala25Thr	missense_variant	3/4	4		ENSP00000391983.2
KLHL10	ENST00000485613.1	n.181G>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.027	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	.;L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.18
MutPred		0.44		Gain of glycosylation at A25 (P = 0.0463);Gain of glycosylation at A25 (P = 0.0463);Gain of glycosylation at A25 (P = 0.0463);
MVP		0.30
MPC		0.60
ClinPred		0.20	T
GERP RS		3.8
Varity_R		0.044
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39994257;