rs200857990

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_015459.5(ATL3):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,583,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ATL3
NM_015459.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Publications

0 publications found

Variant links:

Genes affected

ATL3 (HGNC:24526): (atlastin GTPase 3) This gene encodes a member of a family of dynamin-like, integral membrane GTPases. The encoded protein is required for the proper formation of the network of interconnected tubules of the endoplasmic reticulum. Mutations in this gene may be associated with hereditary sensory neuropathy type IF. Alternatively spliced transcript variants that encode distinct isoforms have been described. [provided by RefSeq, Feb 2014]

ATL3 Gene-Disease associations (from GenCC):

neuropathy, hereditary sensory, type 1F
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
hereditary sensory and autonomic neuropathy type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 19 codons. Genomic position: 63659244. Lost 0.034 part of the original CDS.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL3	NM_015459.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	ENST00000398868.8	NP_056274.3	Q6DD88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATL3	ENST00000398868.8 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	1	NM_015459.5	ENSP00000381844.3	Q6DD88
ATL3	ENST00000540699.1 link	c.158T>C	p.Met53Thr	missense_variant	Exon 2 of 4	3		ENSP00000441842.1	F5GWF8
ATL3	ENST00000535789.1 link	n.413T>C		non_coding_transcript_exon_variant	Exon 1 of 3	4
ATL3	ENST00000538786.1 link	c.-9+302T>C		intron_variant	Intron 1 of 12	2		ENSP00000437593.1	F5H6I7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000983

AC:

AN:

203530

AF XY:

0.00000892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000252

AC:

AN:

1431016

Hom.:

Cov.:

AF XY:

0.0000253

AC XY:

AN XY:

711140

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30020

American (AMR)

AF:

0.0000240

AC:

AN:

41664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.00

AC:

AN:

35532

South Asian (SAS)

AF:

0.00

AC:

AN:

83330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

1098854

Other (OTH)

AF:

0.0000169

AC:

AN:

59062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000859

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory, type 1F

Uncertain:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the ATL3 mRNA. The next in-frame methionine is located at codon 19. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ATL3-related conditions. ClinVar contains an entry for this variant (Variation ID: 577140). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0046

T;T

Eigen

Benign

0.077

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

D;T

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.55

PhyloP100

2.8

PROVEAN

Benign

-0.12

N;N

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;T

Sift4G

Benign

0.085

T;.

Polyphen

0.067

B;P

Vest4

0.92

MVP

0.87

ClinPred

1.0

GERP RS

4.9

PromoterAI

-0.51

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.92

gMVP

0.44

Mutation Taster

=27/173

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over