Genetic Variant ATXN7L1:p.Ala735Val (chr7-105614130-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020725.2(ATXN7L1):c.2204C>T(p.Ala735Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000864 in 1,551,608 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.000092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ATXN7L1
NM_020725.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Variant links:

Genes affected

ATXN7L1 (HGNC:22210): (ataxin 7 like 1)

ATXN7L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0088942945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN7L1	NM_020725.2 link	c.2204C>T	p.Ala735Val	missense_variant	Exon 10 of 12	ENST00000419735.8	NP_065776.1	Q9ULK2-1
ATXN7L1	NM_001385596.1 link	c.2204C>T	p.Ala735Val	missense_variant	Exon 10 of 12		NP_001372525.1
ATXN7L1	NM_138495.2 link	c.1832C>T	p.Ala611Val	missense_variant	Exon 8 of 10		NP_612504.1	Q9ULK2-3
ATXN7L1	NM_001318229.2 link	c.1556C>T	p.Ala519Val	missense_variant	Exon 10 of 10		NP_001305158.1	Q9BTQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN7L1	ENST00000419735.8 link	c.2204C>T	p.Ala735Val	missense_variant	Exon 10 of 12	1	NM_020725.2	ENSP00000410759.3		Q9ULK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000166

AC:

AN:

156260

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

82826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000878

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000331

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000858

AC:

120

AN:

1399288

Hom.:

Cov.:

AF XY:

0.0000913

AC XY:

AN XY:

690126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00147

Gnomad4 EAS exome

AF:

0.000168

Gnomad4 SAS exome

AF:

0.000303

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000343

Gnomad4 OTH exome

AF:

0.000138

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000192

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2204C>T (p.A735V) alteration is located in exon 10 (coding exon 10) of the ATXN7L1 gene. This alteration results from a C to T substitution at nucleotide position 2204, causing the alanine (A) at amino acid position 735 to be replaced by a valine (V). 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

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.00080

T;.;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0089

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.1

N;.;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.56

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.13

MVP

0.36

MPC

0.40

ClinPred

0.041

GERP RS

4.4

Varity_R

0.048

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over