rs397514712

Variant names:

• chr14-50628155-G-A
• rs397514712
• NM_015915.5:c.1244G>A

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.1244G>A​(p.Arg415Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,894 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. R415W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.89
• Publications: 7 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 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_015915.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628154-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP5: Variant 14-50628155-G-A is Pathogenic according to our data. Variant chr14-50628155-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56844.
• BS2: High AC in GnomAdExome4 at 7 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.1244G>A	p.Arg415Gln	missense	Exon 12 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.1244G>A	p.Arg415Gln	missense	Exon 13 of 14	NP_001121185.1
	ATL1	NM_181598.4		c.1244G>A	p.Arg415Gln	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.1244G>A	p.Arg415Gln	missense	Exon 12 of 14	ENSP00000351155.7
	ATL1	ENST00000441560.6	TSL:1	c.1244G>A	p.Arg415Gln	missense	Exon 13 of 14	ENSP00000413675.2
	ATL1	ENST00000682037.1		c.1244G>A	p.Arg415Gln	missense	Exon 12 of 14	ENSP00000508289.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251276 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

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: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000202 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary spastic paraplegia 3A (2)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.88	L
PhyloP100		5.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.43
Sift	Benign	0.57	T
Sift4G	Benign	0.73	T
Polyphen		0.012	B
Vest4		0.74
MutPred		0.45		Loss of MoRF binding (P = 0.0446)
MVP		0.92
MPC		0.76
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.46
gMVP		0.63
Mutation Taster		=2/98	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: rs397514712; hg19: chr14-51094873; COSMIC: COSV104417950; COSMIC: COSV104417950;