chr12-6939123-C-A

Variant names:

• chr12-6939123-C-A
• rs1555144357
• NM_001940.4:c.3160C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001940.4(ATN1):​c.3160C>A​(p.His1054Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1054Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.42

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001940.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 12-6939123-C-A is Pathogenic according to our data. Variant chr12-6939123-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 487496.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-6939123-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.3160C>A	p.His1054Asn	missense_variant	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.3160C>A	p.His1054Asn	missense_variant	Exon 7 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.3160C>A	p.His1054Asn	missense_variant	Exon 7 of 10	1		ENSP00000349076.3
ATN1	ENST00000537488.1	n.17C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
ATN1	ENST00000541029.1	n.*158C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Congenital ATN1 related disorder Pathogenic:1

Jan 04, 2018

Sydney Children's Hospital, SCHN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

affected individual has clinical features consistent with congenital ATN1 related disorder -

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Pathogenic:1

Jul 12, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.98	D;D
Vest4		0.80
MutPred		0.67		Gain of catalytic residue at Q1053 (P = 0.0046);Gain of catalytic residue at Q1053 (P = 0.0046);
MVP		0.87
MPC		2.2
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.83
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555144357; hg19: chr12-7048286;