rs751861796

Variant names:

• chr14-50629999-G-A
• rs751861796
• NM_015915.5:c.1556G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-50629999-G-A
• chr14-50629999-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_015915.5(ATL1):​c.1556G>A​(p.Ser519Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000326 in 1,594,694 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S519T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: 4.27
• Publications: 2 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, Orphanet, Ambry Genetics
• 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_benign. The variant received -4 ACMG points.

• 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.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000592 (9/152106) while in subpopulation NFE AF = 0.000132 (9/68026). AF 95% confidence interval is 0.000068. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_015915.5	MANE Select	c.1556G>A	p.Ser519Asn	missense	Exon 13 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.1551+1537G>A		intron	N/A	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.1551+1537G>A		intron	N/A	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.1556G>A	p.Ser519Asn	missense	Exon 13 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.1551+1537G>A		intron	N/A	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.1600G>A	p.Val534Ile	missense	Exon 13 of 14	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 242362 AF XY: 0.0000153

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: 0.0000458

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000298 AC: 43 AN: 1442588 Hom.: 0 Cov.: 27 AF XY: 0.0000251 AC XY: 18 AN XY: 718042

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 43456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 83606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.0000373 AC: 41 AN: 1098824

Other (OTH) AF: 0.0000168 AC: 1 AN: 59660

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000611 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary spastic paraplegia 3A (2)
-	-	-	Hereditary spastic paraplegia 3A;C3150972:Neuropathy, hereditary sensory, type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.3
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.33
Sift	Benign	0.096	T
Sift4G	Benign	0.22	T
Vest4		0.71
MVP		0.80
MPC		0.62
ClinPred		0.22	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.76
Mutation Taster		=26/74	disease causing

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: rs751861796; hg19: chr14-51096717;