12-6935977-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001940.4(ATN1):c.710G>A(p.Gly237Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G237V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.968

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22636738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.710G>A	p.Gly237Glu	missense_variant	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.710G>A	p.Gly237Glu	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.710G>A	p.Gly237Glu	missense_variant	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.710G>A	p.Gly237Glu	missense_variant	5/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437568 Hom.: 0 Cov.: 38 AF XY: 0.00000140 AC XY: 1 AN XY: 713274

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.22
Sift	Benign	0.043	D;D
Sift4G	Benign	0.36	T;T
Polyphen		0.42	B;B
Vest4		0.45
MutPred		0.29		Gain of catalytic residue at P235 (P = 0.0196);Gain of catalytic residue at P235 (P = 0.0196);
MVP		0.48
MPC		0.48
ClinPred		0.24	T
GERP RS		0.60
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.5
Varity_R		0.068
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7045140;