13-70107609-C-A

Position:

chr13-70107609-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_020866.3(KLHL1):c.91G>T(p.Gly31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,592,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.306

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0067028403).

BP6

Variant 13-70107609-C-A is Benign according to our data. Variant chr13-70107609-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052204.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL1	NM_020866.3 linkuse as main transcript	c.91G>T	p.Gly31Cys	missense_variant	1/11	ENST00000377844.9	NP_065917.1
ATXN8OS	NR_002717.2 linkuse as main transcript	n.397C>A		non_coding_transcript_exon_variant	1/5
KLHL1	NM_001286725.2 linkuse as main transcript	c.91G>T	p.Gly31Cys	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.91G>T	p.Gly31Cys	missense_variant	1/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2 linkuse as main transcript	c.91G>T	p.Gly31Cys	missense_variant	1/10	2		ENSP00000439602
ATXN8OS	ENST00000414504.6 linkuse as main transcript	n.397C>A		non_coding_transcript_exon_variant	1/5	5
ATXN8OS	ENST00000665905.1 linkuse as main transcript	n.281C>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00598

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000508

AC:

114

AN:

224472

Hom.:

AF XY:

0.000379

AC XY:

AN XY:

121440

show subpopulations

Gnomad AFR exome

AF:

0.00683

Gnomad AMR exome

AF:

0.000285

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:

0.00

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.000146

AC:

210

AN:

1439892

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

714744

show subpopulations

Gnomad4 AFR exome

AF:

0.00554

Gnomad4 AMR exome

AF:

0.000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.08e-7

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.00167

AC:

255

AN:

152344

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00596

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.00202

ESP6500AA

AF:

0.00388

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000495

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KLHL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.63

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.76

N;.

REVEL

Benign

0.23

Sift

Benign

0.038

D;.

Sift4G

Benign

0.066

T;T

Polyphen

1.0

D;.

Vest4

0.34

MVP

0.82

MPC

0.25

ClinPred

0.035

GERP RS

2.5

Varity_R

0.092

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