13-70107466-T-C

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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.234A>G	p.Ser78Ser	synonymous_variant	Exon 1 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.234A>G	p.Ser78Ser	synonymous_variant	Exon 1 of 10		NP_001273654.1
ATXN8OS	NR_002717.3	n.46T>C		non_coding_transcript_exon_variant	Exon 1 of 5
ATXN8OS	NR_185842.1	n.46T>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.234A>G	p.Ser78Ser	synonymous_variant	Exon 1 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.234A>G	p.Ser78Ser	synonymous_variant	Exon 1 of 10	2		ENSP00000439602.2
ATXN8OS	ENST00000414504.6	n.254T>C		non_coding_transcript_exon_variant	Exon 1 of 5	5
ATXN8OS	ENST00000665905.1	n.138T>C		non_coding_transcript_exon_variant	Exon 1 of 4

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

Gnomad4 AFR exome AF: 0.221 AC: 7389 AN: 33476

Gnomad4 AMR exome AF: 0.137 AC: 6121 AN: 44722

Gnomad4 ASJ exome AF: 0.0233 AC: 609 AN: 26132

Gnomad4 EAS exome AF: 0.352 AC: 13959 AN: 39700

Gnomad4 SAS exome AF: 0.103 AC: 8873 AN: 86256

Gnomad4 FIN exome AF: 0.119 AC: 6370 AN: 53418

Gnomad4 NFE exome AF: 0.0551 AC: 61311 AN: 1111962

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.216 AC: 0.216373 AN: 0.216373

Gnomad4 AMR AF: 0.0978 AC: 0.0977621 AN: 0.0977621

Gnomad4 ASJ AF: 0.0210 AC: 0.0210496 AN: 0.0210496

Gnomad4 EAS AF: 0.323 AC: 0.322505 AN: 0.322505

Gnomad4 SAS AF: 0.115 AC: 0.115449 AN: 0.115449

Gnomad4 FIN AF: 0.129 AC: 0.128968 AN: 0.128968

Gnomad4 NFE AF: 0.0560 AC: 0.05601 AN: 0.05601

Gnomad4 OTH AF: 0.0880 AC: 0.0879849 AN: 0.0879849

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

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KLHL1-related disorder Benign:1

Jul 18, 2019

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	-0.99
CADD	Benign	0.053
DANN	Benign	0.34
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

Publications

LitVar

Other links and lift over

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