NM_001940.4:c.3178C>T

Variant names:

• chr12-6939141-C-T
• rs797044566
• NM_001940.4:c.3178C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001940.4(ATN1):​c.3178C>T​(p.His1060Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1060T*?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 16 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6939140-GC-GACCTG is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 12-6939141-C-T is Pathogenic according to our data. Variant chr12-6939141-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6939141-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.3178C>T	p.His1060Tyr	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.3178C>T	p.His1060Tyr	missense_variant	Exon 7 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.3178C>T	p.His1060Tyr	missense_variant	Exon 7 of 10	1		ENSP00000349076.3
ATN1	ENST00000537488.1	n.35C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
ATN1	ENST00000541029.1	n.*176C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35363364, 37644014, 30827498, 26112015) -

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

Jul 15, 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	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.98	D;D
Vest4		0.75
MutPred		0.70		Gain of catalytic residue at H1060 (P = 0.0014);Gain of catalytic residue at H1060 (P = 0.0014);
MVP		0.95
MPC		2.3
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.94

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: rs797044566; hg19: chr12-7048304;