Genetic Variant ATXN7L1:p.His753Asp (chr7-105614077-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020725.2(ATXN7L1):c.2257C>G(p.His753Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H753Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ATXN7L1
NM_020725.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.92

Publications

0 publications found

Variant links:

Genes affected

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

ATXN7L1 links:

ENSG00000295921 (HGNC:):

ENSG00000295921 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29063493).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020725.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN7L1	NM_020725.2	MANE Select	c.2257C>G	p.His753Asp	missense	Exon 10 of 12	NP_065776.1	Q9ULK2-1
ATXN7L1	NM_001385596.1		c.2257C>G	p.His753Asp	missense	Exon 10 of 12	NP_001372525.1
ATXN7L1	NM_138495.2		c.1885C>G	p.His629Asp	missense	Exon 8 of 10	NP_612504.1	Q9ULK2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN7L1	ENST00000419735.8	TSL:1 MANE Select	c.2257C>G	p.His753Asp	missense	Exon 10 of 12	ENSP00000410759.3	Q9ULK2-1
ATXN7L1	ENST00000484475.5	TSL:1	c.1360C>G	p.His454Asp	missense	Exon 4 of 4	ENSP00000418900.1	H0Y8A2
ATXN7L1	ENST00000474433.5	TSL:1	n.*1832C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000420483.1	F8WDE7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.00032

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0098

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Benign

0.043

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.2

PhyloP100

6.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Benign

0.070

Sift4G

Benign

0.57

Polyphen

0.78

Vest4

0.64

MutPred

0.14

Gain of loop (P = 0.0312)

MVP

0.74

MPC

1.2

ClinPred

0.86

GERP RS

3.2

Varity_R

0.23

gMVP

0.50

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over