rs1555144358

Positions:

• chr12-6939135-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001940.4(ATN1):​c.3172C>T​(p.His1058Tyr) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.87

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, 4 uncertain in NM_001940.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• PP5: Variant 12-6939135-C-T is Pathogenic according to our data. Variant chr12-6939135-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 487497.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6939135-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.3172C>T	p.His1058Tyr	missense_variant	7/10	ENST00000396684.3
ATN1	NM_001007026.2	c.3172C>T	p.His1058Tyr	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.3172C>T	p.His1058Tyr	missense_variant	7/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.3172C>T	p.His1058Tyr	missense_variant	7/10	1		P1
ATN1	ENST00000537488.1	n.29C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital ATN1 related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Children's Hospital, SCHN

Jan 04, 2018

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

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 12, 2019

- -

ATN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a de novo heterozygous change in a patient with congenital hypotonia, abnormal EEG, developmental delay, and polymicrogyria on brain MRI (PMID: 30827498). The c.3172C>T (p.His1058Tyr) variant is located in the HX Repeat Motif of the ATN1 gene, which is a mutational hotspot for pathogenic variations associated with neurodevelopmental phenotypes (PMID: 30827498). The c.3172C>T (p.His1058Tyr) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3172C>T (p.His1058Tyr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.3172C>T (p.His1058Tyr) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.010	B;B
Vest4		0.74
MutPred		0.68		Gain of catalytic residue at Q1053 (P = 8e-04);Gain of catalytic residue at Q1053 (P = 8e-04);
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555144358; hg19: chr12-7048298;