rs387906941

Variant names:

• chr14-50628157-C-T
• rs387906941
• NM_015915.5:c.1246C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1 PM5 PP2 PP5 BS2

The NM_015915.5(ATL1):​c.1246C>T​(p.Arg416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 3.23
• Publications: 11 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_015915.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628158-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 858305.
• 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.
• PP5: Variant 14-50628157-C-T is Pathogenic according to our data. Variant chr14-50628157-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30582.
• BS2: High AC in GnomAdExome4 at 9 AD,SD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_015915.5	MANE Select	c.1246C>T	p.Arg416Cys	missense	Exon 12 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.1246C>T	p.Arg416Cys	missense	Exon 13 of 14	NP_001121185.1
	ATL1	NM_181598.4		c.1246C>T	p.Arg416Cys	missense	Exon 12 of 13	NP_853629.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.1246C>T	p.Arg416Cys	missense	Exon 12 of 14	ENSP00000351155.7
	ATL1	ENST00000441560.6	TSL:1	c.1246C>T	p.Arg416Cys	missense	Exon 13 of 14	ENSP00000413675.2
	ATL1	ENST00000682037.1		c.1246C>T	p.Arg416Cys	missense	Exon 12 of 14	ENSP00000508289.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251296 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.61
Sift	Benign	0.045	D
Sift4G	Uncertain	0.059	T
Polyphen		0.60	P
Vest4		0.76
MutPred		0.54		Loss of disorder (P = 0.0138)
MVP		0.93
MPC		0.91
ClinPred		0.58	D
GERP RS		4.9
Varity_R		0.51
gMVP		0.67
Mutation Taster		=3/97	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: rs387906941; hg19: chr14-51094875; COSMIC: COSV63296295; COSMIC: COSV63296295;