chr14-50595596-A-C

Variant names:

• chr14-50595596-A-C
• rs1555364247
• NM_015915.5:c.594A>C

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.594A>C​(p.Arg198Ser) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.627

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain GB1/RHD3-type G (size 245) in uniprot entity ATLA1_HUMAN there are 38 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 the ATL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 60 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.6313 (below the threshold of 3.09). Trascript score misZ: 3.8383 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 14-50595596-A-C is Pathogenic according to our data. Variant chr14-50595596-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 471250.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.594A>C	p.Arg198Ser	missense_variant	Exon 6 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.594A>C	p.Arg198Ser	missense_variant	Exon 7 of 14		NP_001121185.1
ATL1	NM_181598.4	c.594A>C	p.Arg198Ser	missense_variant	Exon 6 of 13		NP_853629.2
ATL1	XM_047431430.1	c.594A>C	p.Arg198Ser	missense_variant	Exon 7 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.594A>C	p.Arg198Ser	missense_variant	Exon 6 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1

May 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with serine at codon 198 of the ATL1 protein (p.Arg198Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with hereditary spastic paraplegia (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;D;T
Eigen	Benign	0.098
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.85	.;P;.
Vest4		0.85
MutPred		0.81		Loss of methylation at R198 (P = 0.078);Loss of methylation at R198 (P = 0.078);.;
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		-1.9
Varity_R		0.97
gMVP		0.93

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: rs1555364247; hg19: chr14-51062314;