NM_001940.4:c.281A>T

Variant names:

• chr12-6935548-A-T
• rs782062902
• NM_001940.4:c.281A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001940.4(ATN1):​c.281A>T​(p.Gln94Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,455,242 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATN1 NM_001940.4 missense, splice_region
• Scores: Splicing: ADA: 0.01524
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.68

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 2 ACMG points.

• 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.281A>T	p.Gln94Leu	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.281A>T	p.Gln94Leu	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.281A>T	p.Gln94Leu	missense_variant, splice_region_variant	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248740 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455242 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 722692

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.55	.;T
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.049	D;D
Polyphen		0.99	D;D
Vest4		0.55
MutPred		0.43		Gain of catalytic residue at L96 (P = 0.0016);Gain of catalytic residue at L96 (P = 0.0016);
MVP		0.41
MPC		0.30
ClinPred		0.81	D
GERP RS		4.0
Varity_R		0.25
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.13
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: rs782062902; hg19: chr12-7044711;