14-50614422-A-T

Position:

• chr14-50614422-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_015915.5(ATL1):​c.773A>T​(p.His258Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H258R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.40

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ATLA1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50614422-A-G is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 14-50614422-A-T is Pathogenic according to our data. Variant chr14-50614422-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1456145.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.773A>T	p.His258Leu	missense_variant	8/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.773A>T	p.His258Leu	missense_variant	9/14		NP_001121185.1
ATL1	NM_181598.4	c.773A>T	p.His258Leu	missense_variant	8/13		NP_853629.2
ATL1	XM_047431430.1	c.773A>T	p.His258Leu	missense_variant	9/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.773A>T	p.His258Leu	missense_variant	8/14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2021

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His258 ‚Äãamino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11685207). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with clinical features of autosomal dominant ATL1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces histidine with leucine at codon 258 of the ATL1 protein (p.His258Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.54	.;D
Eigen	Benign	-0.0043
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.62
Sift	Benign	0.072	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0010	.;B
Vest4		0.57
MutPred		0.66		Loss of disorder (P = 0.0479);Loss of disorder (P = 0.0479);
MVP		0.95
MPC		0.83
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-51081140;