rs144867124

Variant names:

• chr13-70107689-G-C
• rs144867124
• NM_020866.3:c.11C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-70107689-G-C
• chr13-70107689-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52
• Publications: 3 publications found

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]

ATXN8OS Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29450536).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020866.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL1	NM_020866.3	MANE Select	c.11C>G	p.Ser4Cys	missense	Exon 1 of 11	NP_065917.1	Q9NR64
	KLHL1	NM_001286725.2		c.11C>G	p.Ser4Cys	missense	Exon 1 of 10	NP_001273654.1	F5H1J3
	ATXN8OS	NR_002717.3		n.269G>C		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL1	ENST00000377844.9	TSL:1 MANE Select	c.11C>G	p.Ser4Cys	missense	Exon 1 of 11	ENSP00000367075.4	Q9NR64
	KLHL1	ENST00000545028.2	TSL:2	c.11C>G	p.Ser4Cys	missense	Exon 1 of 10	ENSP00000439602.2	F5H1J3
	ATXN8OS	ENST00000414504.6	TSL:5	n.477G>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152190 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000398 AC: 69 AN: 173398 AF XY: 0.000347

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 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.: 0 Cov.: 33 AF XY: 0.000686 AC XY: 463 AN XY: 675400

African (AFR) AF: 0.000262 AC: 8 AN: 30554

American (AMR) AF: 0.000548 AC: 17 AN: 30994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20198

East Asian (EAS) AF: 0.00 AC: 0 AN: 39100

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71448

European-Finnish (FIN) AF: 0.000107 AC: 5 AN: 46734

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5136

European-Non Finnish (NFE) AF: 0.000858 AC: 921 AN: 1073752

Other (OTH) AF: 0.000831 AC: 47 AN: 56582

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74354

African (AFR) AF: 0.000217 AC: 9 AN: 41474

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.000356 AC: 42

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.96
MPC		0.36
ClinPred		0.062	T
GERP RS		5.3
Varity_R		0.31
gMVP		0.30
Mutation Taster		=71/29	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

Other links and lift over

dbSNP: rs144867124; hg19: chr13-70681821;