Variant 13-70107689-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020866.3(KLHL1):c.11C>G(p.Ser4Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000692 in 1,526,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.52

Variant links:

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]

KLHL1 links:

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]

ATXN8OS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.29450536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL1	NM_020866.3 linkuse as main transcript	c.11C>G	p.Ser4Cys	missense_variant	1/11	ENST00000377844.9	NP_065917.1
ATXN8OS	NR_002717.2 linkuse as main transcript	n.477G>C		non_coding_transcript_exon_variant	1/5
KLHL1	NM_001286725.2 linkuse as main transcript	c.11C>G	p.Ser4Cys	missense_variant	1/10		NP_001273654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KLHL1	ENST00000377844.9 linkuse as main transcript	c.11C>G	p.Ser4Cys	missense_variant	1/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2 linkuse as main transcript	c.11C>G	p.Ser4Cys	missense_variant	1/10	2		ENSP00000439602
ATXN8OS	ENST00000414504.6 linkuse as main transcript	n.477G>C		non_coding_transcript_exon_variant	1/5	5
ATXN8OS	ENST00000665905.1 linkuse as main transcript	n.361G>C		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000398

AC:

AN:

173398

Hom.:

AF XY:

0.000347

AC XY:

AN XY:

92210

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.000358

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:

0.000637

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000728

AC:

1000

AN:

1374498

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

463

AN XY:

675400

show subpopulations

Gnomad4 AFR exome

AF:

0.000262

Gnomad4 AMR exome

AF:

0.000548

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000140

Gnomad4 FIN exome

AF:

0.000107

Gnomad4 NFE exome

AF:

0.000858

Gnomad4 OTH exome

AF:

0.000831

GnomAD4 genome

AF:

0.000368

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000675

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000356

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.11C>G (p.S4C) alteration is located in exon 1 (coding exon 1) of the KLHL1 gene. This alteration results from a C to G substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a cysteine (C). 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

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.99

N;.

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.46

MVP

0.96

MPC

0.36

ClinPred

0.062

GERP RS

5.3

Varity_R

0.31

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over