12-6935815-T-G

Variant summary

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

The NM_001940.4(ATN1):c.548T>G(p.Phe183Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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/exons	MANE	UniProt
ATN1	NM_001940.4	c.548T>G	p.Phe183Cys	missense_variant	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.548T>G	p.Phe183Cys	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.548T>G	p.Phe183Cys	missense_variant	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.548T>G	p.Phe183Cys	missense_variant	5/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461720 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The c.548T>G (p.F183C) alteration is located in exon 5 (coding exon 4) of the ATN1 gene. This alteration results from a T to G substitution at nucleotide position 548, causing the phenylalanine (F) at amino acid position 183 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.018
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.065	T;T
Polyphen		0.98	D;D
Vest4		0.61
MutPred		0.35		Gain of catalytic residue at H186 (P = 0.0721);Gain of catalytic residue at H186 (P = 0.0721);
MVP		0.56
MPC		0.50
ClinPred		0.57	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.37

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: chr12-7044978;