Genetic Variant KLHL1:p.Ser124Ser (chr13-70107328-T-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_020866.3(KLHL1):c.372A>C(p.Ser124Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

KLHL1
NM_020866.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.721

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 13-70107328-T-G is Benign according to our data. Variant chr13-70107328-T-G is described in ClinVar as [Benign]. Clinvar id is 790680.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.721 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3 link	c.372A>C	p.Ser124Ser	synonymous_variant	Exon 1 of 11	ENST00000377844.9	NP_065917.1	Q9NR64Q8TBJ7
KLHL1	NM_001286725.2 link	c.372A>C	p.Ser124Ser	synonymous_variant	Exon 1 of 10		NP_001273654.1	Q9NR64F5H1J3Q8TBJ7B7Z3I8
ATXN8OS	NR_002717.3 link	n.-93T>G		upstream_gene_variant
ATXN8OS	NR_185842.1 link	n.-93T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL1	ENST00000377844.9 link	c.372A>C	p.Ser124Ser	synonymous_variant	Exon 1 of 11	1	NM_020866.3	ENSP00000367075.4	Q9NR64
KLHL1	ENST00000545028.2 link	c.372A>C	p.Ser124Ser	synonymous_variant	Exon 1 of 10	2		ENSP00000439602.2	F5H1J3
ATXN8OS	ENST00000414504.6 link	n.116T>G		non_coding_transcript_exon_variant	Exon 1 of 5	5
ATXN8OS	ENST00000665905.1 link	n.-1T>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

342

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00775

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000582

AC:

146

AN:

251010

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000248

AC:

362

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

160

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00833

AC:

279

AN:

33480

Gnomad4 AMR exome

AF:

0.000648

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53410

Gnomad4 NFE exome

AF:

0.00000360

AC:

AN:

1112000

Gnomad4 Remaining exome

AF:

0.000762

AC:

AN:

60392

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00227

AC:

346

AN:

152292

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00782

AC:

0.00781851

AN:

0.00781851

Gnomad4 AMR

AF:

0.00124

AC:

0.00124264

AN:

0.00124264

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000945

AC:

0.00094518

AN:

0.00094518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000933

Hom.:

Bravo

AF:

0.00250

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KLHL1-related disorder

Benign:1

Aug 28, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.0

DANN

Benign

0.80

Mutation Taster

=298/2

polymorphism

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