Genetic Variant KLHL1:p.Ala33Ala (chr13-70107601-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_020866.3(KLHL1):c.99G>A(p.Ala33Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,593,632 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 5 hom. )

Consequence

KLHL1
NM_020866.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.281

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 13-70107601-C-T is Benign according to our data. Variant chr13-70107601-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1176326.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.281 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3 link	c.99G>A	p.Ala33Ala	synonymous_variant	Exon 1 of 11	ENST00000377844.9	NP_065917.1	Q9NR64Q8TBJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9 link	c.99G>A	p.Ala33Ala	synonymous_variant	Exon 1 of 11	1	NM_020866.3	ENSP00000367075.4		Q9NR64

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000988

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00171

AC:

385

AN:

225160

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.000538

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.000394

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00183

Gnomad NFE exome

AF:

0.00264

Gnomad OTH exome

AF:

0.00224

GnomAD4 exome

AF:

0.00248

AC:

3576

AN:

1441280

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1799

AN XY:

715534

show subpopulations

Gnomad4 AFR exome

AF:

0.000425

AC:

AN:

32916

Gnomad4 AMR exome

AF:

0.00135

AC:

AN:

42340

Gnomad4 ASJ exome

AF:

0.000290

AC:

AN:

24162

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39616

Gnomad4 SAS exome

AF:

0.000605

AC:

AN:

82690

Gnomad4 FIN exome

AF:

0.00168

AC:

AN:

52358

Gnomad4 NFE exome

AF:

0.00291

AC:

3211

AN:

1102194

Gnomad4 Remaining exome

AF:

0.00249

AC:

148

AN:

59418

Heterozygous variant carriers

213

426

638

851

1064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00200

AC:

305

AN:

152352

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000985

AC:

0.000985482

AN:

0.000985482

Gnomad4 AMR

AF:

0.00137

AC:

0.00137183

AN:

0.00137183

Gnomad4 ASJ

AF:

0.000576

AC:

0.000576037

AN:

0.000576037

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000206868

AN:

0.000206868

Gnomad4 FIN

AF:

0.000565

AC:

0.000564865

AN:

0.000564865

Gnomad4 NFE

AF:

0.00331

AC:

0.00330785

AN:

0.00330785

Gnomad4 OTH

AF:

0.00142

AC:

0.00141911

AN:

0.00141911

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:

0.00122

Hom.:

Bravo

AF:

0.00200

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLHL1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

5.9

DANN

Benign

0.88

Mutation Taster

=299/1

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