14-50629999-G-C

Variant names:

• chr14-50629999-G-C
• NM_015915.5:c.1556G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_015915.5(ATL1):​c.1556G>C​(p.Ser519Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S519N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50629999-G-A is described in Lovd as [Pathogenic].
• 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 sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22904348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1556G>C	p.Ser519Thr	missense_variant	Exon 13 of 14	ENST00000358385.12	NP_056999.2
ATL1	XM_047431430.1	c.1556G>C	p.Ser519Thr	missense_variant	Exon 14 of 15		XP_047287386.1
ATL1	NM_001127713.1	c.1551+1537G>C		intron_variant	Intron 13 of 13		NP_001121185.1
ATL1	NM_181598.4	c.1551+1537G>C		intron_variant	Intron 12 of 12		NP_853629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1556G>C	p.Ser519Thr	missense_variant	Exon 13 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATL1: PM2, PM5:Supporting, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.30
Sift	Benign	0.53	T
Sift4G	Benign	0.86	T
Vest4		0.34
MutPred		0.30		Gain of glycosylation at T520 (P = 0.1805);
MVP		0.81
MPC		0.60
ClinPred		0.30	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-51096717;