rs119476048

Positions:

• chr14-50614422-A-G
• chr14-50614422-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_015915.5(ATL1):​c.773A>G​(p.His258Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O: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
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 14-50614422-A-G is Pathogenic according to our data. Variant chr14-50614422-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50614422-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.773A>G	p.His258Arg	missense_variant	8/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.773A>G	p.His258Arg	missense_variant	9/14		NP_001121185.1
ATL1	NM_181598.4	c.773A>G	p.His258Arg	missense_variant	8/13		NP_853629.2
ATL1	XM_047431430.1	c.773A>G	p.His258Arg	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>G	p.His258Arg	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:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2019	This sequence change replaces histidine with arginine at codon 258 of the ATL1 protein (p.His258Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to have conflicting or insufficient data to determine the effect on ATL1 protein function (PMID: 16537571, 25761634). This variant has been observed to segregate with hereditary spastic paraplegia in a family (PMID: 11685207). ClinVar contains an entry for this variant (Variation ID: 4348). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Benign	0.40
DEOGEN2	Benign	0.23	.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.82	L;L
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.84	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.68
MutPred		0.87		Gain of MoRF binding (P = 0.0345);Gain of MoRF binding (P = 0.0345);
MVP		0.98
MPC		0.81
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.75

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

Other links and lift over

dbSNP: rs119476048; hg19: chr14-51081140;