rs1555143468

Variant names:

• chr12-6935763-C-A
• rs1555143468
• NM_001940.4:c.496C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6935763-C-A
• chr12-6935763-C-G
• chr12-6935763-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001940.4(ATN1):​c.496C>A​(p.Pro166Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P166A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 0 publications found

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]

ATN1 Gene-Disease associations (from GenCC):

• congenital hypotonia, epilepsy, developmental delay, and digital anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• dentatorubral-pallidoluysian atrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3175273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001940.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	NM_001940.4	MANE Select	c.496C>A	p.Pro166Thr	missense	Exon 5 of 10	NP_001931.2	P54259
	ATN1	NM_001007026.2		c.496C>A	p.Pro166Thr	missense	Exon 5 of 10	NP_001007027.1	P54259
	ATN1	NM_001424176.1		c.496C>A	p.Pro166Thr	missense	Exon 5 of 10	NP_001411105.1	P54259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	ENST00000396684.3	TSL:1 MANE Select	c.496C>A	p.Pro166Thr	missense	Exon 5 of 10	ENSP00000379915.2	P54259
	ATN1	ENST00000356654.8	TSL:1	c.496C>A	p.Pro166Thr	missense	Exon 5 of 10	ENSP00000349076.3	P54259
	ATN1	ENST00000882240.1		c.496C>A	p.Pro166Thr	missense	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.052	T
Polyphen		0.95	P
Vest4		0.43
MutPred		0.41		Gain of catalytic residue at L164 (P = 5e-04)
MVP		0.38
MPC		0.45
ClinPred		0.61	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.42
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1555143468; hg19: chr12-7044926;