14-50632302-C-T

Position:

chr14-50632302-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_015915.5(ATL1):c.1640C>T(p.Ser547Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. S547S) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ATL1
NM_015915.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

Variant links:

Genes affected

ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ATL1 links:

SAV1 (HGNC:17795): (salvador family WW domain containing protein 1) WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein with two WW domains, a SARAH domain, and a coiled-coil region and is ubiquitously expressed in adult tissues. This protein binds to MST1 (mammalian sterile 20-like kinase 1) and promotes MST1-induced apoptosis. It has also been shown to bind to HAX1 (hematopoietic cell-specific protein 1 (HS1)-associated protein X-1) and to attenuate the anti-apoptotic effects of HAX1. Studies in human and mouse suggest this gene acts as a tumor suppressor. [provided by RefSeq, Aug 2012]

SAV1 links:

ATL1 (HGNC:):

ATL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATL1. . Gene score misZ 2.6313 (greater than the threshold 3.09). Trascript score misZ 3.8383 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.

BP4

Computational evidence support a benign effect (MetaRNN=0.10516068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5 linkuse as main transcript	c.1640C>T	p.Ser547Leu	missense_variant	14/14	ENST00000358385.12	NP_056999.2	Q8WXF7-1A0A0S2Z5B0Q53F53
ATL1	NM_001127713.1 linkuse as main transcript	c.1625C>T	p.Ser542Leu	missense_variant	14/14		NP_001121185.1	Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1	NM_181598.4 linkuse as main transcript	c.1625C>T	p.Ser542Leu	missense_variant	13/13		NP_853629.2	Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1	XM_047431430.1 linkuse as main transcript	c.1640C>T	p.Ser547Leu	missense_variant	15/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12 linkuse as main transcript	c.1640C>T	p.Ser547Leu	missense_variant	14/14	1	NM_015915.5	ENSP00000351155.7		Q8WXF7-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250870

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461012

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726856

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 3A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2021

This sequence change replaces serine with leucine at codon 547 of the ATL1 protein (p.Ser547Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs778692077, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant ATL1-related conditions (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATL1 protein function. 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

0.069

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

.;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.26

Sift

Benign

0.27

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.20

.;B

Vest4

0.20

MutPred

0.14

.;Loss of relative solvent accessibility (P = 0.0186);

MVP

0.59

MPC

0.59

ClinPred

0.16

GERP RS

4.9

Varity_R

0.14

gMVP

0.42

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

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