rs864622083

Variant names:

• chr14-50628104-C-A
• rs864622083
• NM_015915.5:c.1193C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-50628104-C-A
• chr14-50628104-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_015915.5(ATL1):​c.1193C>A​(p.Ser398Tyr) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S398F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.08
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 3A

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neuropathy, hereditary sensory, type 1D

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr14-50628104-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2571511.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 14-50628104-C-A is Pathogenic according to our data. Variant chr14-50628104-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 219428.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.1193C>A	p.Ser398Tyr	missense_variant	Exon 12 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1193C>A	p.Ser398Tyr	missense_variant	Exon 13 of 14		NP_001121185.1
ATL1	NM_181598.4	c.1193C>A	p.Ser398Tyr	missense_variant	Exon 12 of 13		NP_853629.2
ATL1	XM_047431430.1	c.1193C>A	p.Ser398Tyr	missense_variant	Exon 13 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1193C>A	p.Ser398Tyr	missense_variant	Exon 12 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1 Uncertain:1

Jul 06, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Likely Pathogenic. A different missense substitution at this codon (p.Ser398Phe) is reported to be deleterious (PMID: 19735987). This suggests that the serine residue is important for ATL1 protein function. This variant has been reported in the literature and is not present in population databases. This variant was reported in an individual affected with autosomal dominant hereditary spastic paraplegia, although it is unclear if this variant segregated with disease (PMID: 15596607). This sequence change replaces serine with tyrosine at codon 398 of the ATL1 protein (p.Ser398Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		6.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	.;D
Vest4		0.87
MutPred		0.83		Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);
MVP		0.78
MPC		1.6
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864622083; hg19: chr14-51094822;