1-109490081-C-G

Position:

• chr1-109490081-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001350175.2(ATXN7L2):​c.1285C>G​(p.Pro429Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 1,445,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: ATXN7L2 NM_001350175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.586

Genes affected

ATXN7L2 (HGNC:28713): (ataxin 7 like 2)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038641393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN7L2	NM_001350175.2	c.1285C>G	p.Pro429Ala	missense_variant	8/11	ENST00000683729.1	NP_001337104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN7L2	ENST00000683729.1	c.1285C>G	p.Pro429Ala	missense_variant	8/11		NM_001350175.2	ENSP00000507259	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000854 AC: 2 AN: 234254 Hom.: 0 AF XY: 0.00000791 AC XY: 1 AN XY: 126488

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: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000899 AC: 13 AN: 1445564 Hom.: 0 Cov.: 31 AF XY: 0.00000836 AC XY: 6 AN XY: 717914

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: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2021

The c.1189C>G (p.P397A) alteration is located in exon 8 (coding exon 8) of the ATXN7L2 gene. This alteration results from a C to G substitution at nucleotide position 1189, causing the proline (P) at amino acid position 397 to be replaced by an alanine (A). 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	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.056
Sift	Benign	0.68	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.23		Loss of catalytic residue at P397 (P = 0.0226);
MVP		0.082
MPC		0.29
ClinPred		0.17	T
GERP RS		5.8
Varity_R		0.083
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs778459954; hg19: chr1-110032703;