NM_020866.3:c.234A>G

Variant names:

• chr13-70107466-T-C
• rs3751427
• NM_020866.3:c.234A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_020866.3(KLHL1):​c.234A>G​(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0792 in 1,613,850 control chromosomes in the GnomAD database, including 8,263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1610 hom., cov: 32)
  • Exomes 𝑓: 0.075 (6653 hom.)
• Consequence: KLHL1 NM_020866.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.97
• Publications: 10 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 13-70107466-T-C is Benign according to our data. Variant chr13-70107466-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059673.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-4.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

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.234A>G	p.Ser78Ser	synonymous	Exon 1 of 11	NP_065917.1	Q9NR64
	KLHL1	NM_001286725.2		c.234A>G	p.Ser78Ser	synonymous	Exon 1 of 10	NP_001273654.1	F5H1J3
	ATXN8OS	NR_002717.3		n.46T>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.234A>G	p.Ser78Ser	synonymous	Exon 1 of 11	ENSP00000367075.4	Q9NR64
	KLHL1	ENST00000545028.2	TSL:2	c.234A>G	p.Ser78Ser	synonymous	Exon 1 of 10	ENSP00000439602.2	F5H1J3
	ATXN8OS	ENST00000414504.6	TSL:5	n.254T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18087 AN: 151904 Hom.: 1600 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0974

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0874

GnomAD2 exomes AF: 0.111 AC: 27586 AN: 249300 AF XY: 0.104

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0589

Gnomad OTH exome AF: 0.0809

GnomAD4 exome AF: 0.0750 AC: 109658 AN: 1461830 Hom.: 6653 Cov.: 34 AF XY: 0.0748 AC XY: 54397 AN XY: 727226

African (AFR) AF: 0.221 AC: 7389 AN: 33476

American (AMR) AF: 0.137 AC: 6121 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 609 AN: 26132

East Asian (EAS) AF: 0.352 AC: 13959 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8873 AN: 86256

European-Finnish (FIN) AF: 0.119 AC: 6370 AN: 53418

Middle Eastern (MID) AF: 0.0374 AC: 216 AN: 5768

European-Non Finnish (NFE) AF: 0.0551 AC: 61311 AN: 1111962

Other (OTH) AF: 0.0796 AC: 4810 AN: 60396

GnomAD4 genome AF: 0.119 AC: 18121 AN: 152020 Hom.: 1610 Cov.: 32 AF XY: 0.122 AC XY: 9084 AN XY: 74294

African (AFR) AF: 0.216 AC: 8973 AN: 41470

American (AMR) AF: 0.0978 AC: 1494 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1648 AN: 5110

South Asian (SAS) AF: 0.115 AC: 556 AN: 4816

European-Finnish (FIN) AF: 0.129 AC: 1365 AN: 10584

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3807 AN: 67970

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.0771 Hom.: 360

Bravo AF: 0.125

Asia WGS AF: 0.204 AC: 709 AN: 3478

EpiCase AF: 0.0469

EpiControl AF: 0.0479

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KLHL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.053
DANN	Benign	0.34
PhyloP100		-5.0
Mutation Taster		=299/1	polymorphism (auto)

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: rs3751427; hg19: chr13-70681598; COSMIC: COSV64779733; COSMIC: COSV64779733;