rs119476046

Variant names:

• chr14-50613343-C-T
• rs119476046
• NM_015915.5:c.715C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-50613343-C-T
• chr14-50613343-C-A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_015915.5(ATL1):​c.715C>T​(p.Arg239Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000259322: Experimental studies have shown that this missense change affects ATL1 function (PMID:16537571, 20816793, 23079343)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:2
• Conservation: PhyloP100: 2.50
• Publications: 42 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• neuropathy, hereditary sensory, type 1D

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000259322: Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 20816793, 23079343).; SCV000803456: PS3 downgraded in strength to Moderate (PMID:17321752).; SCV001362053: The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013).; SCV004812317: Functional assays in heterologous systems showed impaired GTPase activity, and altered endoplasmic reticulum and Golgi morphology indicating that this variant impacts protein function (PMID: 16537571, 17321752).; SCV004933975: Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 17321752, 20816793, 23079343).; SCV000279438: Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); SCV000612432: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23079343)
• PM1: In a hotspot region, there are 2 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 chr14-50613344-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1017361.
• 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, 0.954
• PP5: Variant 14-50613343-C-T is Pathogenic according to our data. Variant chr14-50613343-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015915.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_015915.5	MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 7 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.715C>T	p.Arg239Cys	missense	Exon 8 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.715C>T	p.Arg239Cys	missense	Exon 7 of 13	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 7 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.715C>T	p.Arg239Cys	missense	Exon 8 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.715C>T	p.Arg239Cys	missense	Exon 7 of 14	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460004 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726406

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110834

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Hereditary spastic paraplegia 3A (15)
4	-	-	not provided (4)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Hereditary spastic paraplegia 3A;C3150972:Neuropathy, hereditary sensory, type 1D (2)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.50
Sift	Benign	0.037	D
Sift4G	Uncertain	0.054	T
Polyphen		0.76	P
Vest4		0.86
MutPred		0.87		Loss of disorder (P = 0.0112)
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs119476046; hg19: chr14-51080061; COSMIC: COSV63296065; COSMIC: COSV63296065;