14-50613343-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_015915.5(ATL1):​c.715C>A​(p.Arg239Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• 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, 0.898

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>A	p.Arg239Ser	missense	Exon 7 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.715C>A	p.Arg239Ser	missense	Exon 8 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.715C>A	p.Arg239Ser	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>A	p.Arg239Ser	missense	Exon 7 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.715C>A	p.Arg239Ser	missense	Exon 8 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.715C>A	p.Arg239Ser	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: 0.00 AC XY: 0 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.023	D
Polyphen		0.78	P
Vest4		0.88
MutPred		0.74		Gain of disorder (P = 0.0376)
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.94
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;