13-70107545-C-T

Position:

• chr13-70107545-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020866.3(KLHL1):​c.155G>A​(p.Ser52Asn) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

ATXN8OS (HGNC:10561): (ATXN8 opposite strand lncRNA) This gene is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not itself appear to be protein coding. A TAC/TGC trinucleotide repeat expansion that is incorporated into this gene transcript, but not the KLHL1 transcript, causes spinocerebellar ataxia type 8. Presumably the expansion interferes with normal antisense function of this transcript. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31666797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.155G>A	p.Ser52Asn	missense_variant	1/11	ENST00000377844.9	NP_065917.1
ATXN8OS	NR_002717.2	n.333C>T		non_coding_transcript_exon_variant	1/5
KLHL1	NM_001286725.2	c.155G>A	p.Ser52Asn	missense_variant	1/10		NP_001273654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.155G>A	p.Ser52Asn	missense_variant	1/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2	c.155G>A	p.Ser52Asn	missense_variant	1/10	2		ENSP00000439602
ATXN8OS	ENST00000414504.6	n.333C>T		non_coding_transcript_exon_variant	1/5	5
ATXN8OS	ENST00000665905.1	n.217C>T		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.155G>A (p.S52N) alteration is located in exon 1 (coding exon 1) of the KLHL1 gene. This alteration results from a G to A substitution at nucleotide position 155, causing the serine (S) at amino acid position 52 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.52	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.22
Sift	Benign	0.071	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.97	D;.
Vest4		0.36
MutPred		0.23		Gain of catalytic residue at W49 (P = 0);Gain of catalytic residue at W49 (P = 0);
MVP		0.84
MPC		0.098
ClinPred		0.43	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.32

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: rs1888101265; hg19: chr13-70681677; COSMIC: COSV64782898; COSMIC: COSV64782898;