12-6939139-C-CGGACCT

Variant names:

• chr12-6939139-C-CGGACCT
• rs1064795494
• NM_001940.4:c.3177_3178insGACCTG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001940.4(ATN1):​c.3177_3178insGACCTG​(p.Ser1059_His1060insAspLeu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATN1 NM_001940.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04

Genes affected

ATN1 (HGNC:3033): (atrophin 1) Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest HX repeat (size 16) in uniprot entity ATN1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001940.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.3177_3178insGACCTG	p.Ser1059_His1060insAspLeu	conservative_inframe_insertion	Exon 7 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.3177_3178insGACCTG	p.Ser1059_His1060insAspLeu	conservative_inframe_insertion	Exon 7 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.3177_3178insGACCTG	p.Ser1059_His1060insAspLeu	conservative_inframe_insertion	Exon 7 of 10	1		ENSP00000349076.3
ATN1	ENST00000537488.1	n.34_35insGACCTG		non_coding_transcript_exon_variant	Exon 1 of 3	2
ATN1	ENST00000541029.1	n.*174_*175insGGACCT		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 17, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3177_3178insGACCTG variant in the ATN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3177_3178insGACCTG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.3177_3178insGACCTG variant causes an in-frame insertion of two incorrect amino acid residues, denoted p.Ser1059_His1060insAspLeu. To date only trinucleotide repeat expansions have been reported in the Human Gene Mutation Database in association with ATN1-related disorders (Stenson et al., 2014). We interpret c.3177_3178insGACCTG as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064795494; hg19: chr12-7048302;