NM_015915.5:c.33G>C

Variant names:

• chr14-50560298-G-C
• rs765421231
• NM_015915.5:c.33G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_015915.5(ATL1):​c.33G>C​(p.Trp11Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000109 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense, splice_region
• Scores: Splicing: ADA: 0.01124
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93
• 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]

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23456874).
• BS2: High AC in GnomAdExome4 at 16 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.33G>C	p.Trp11Cys	missense splice_region	Exon 1 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.33G>C	p.Trp11Cys	missense splice_region	Exon 2 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.33G>C	p.Trp11Cys	missense splice_region	Exon 1 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.33G>C	p.Trp11Cys	missense splice_region	Exon 1 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.33G>C	p.Trp11Cys	missense splice_region	Exon 2 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.33G>C	p.Trp11Cys	missense splice_region	Exon 1 of 14	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249100 AF XY: 0.0000297

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: 0.0000358

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461568 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111844

Other (OTH) AF: 0.0000331 AC: 2 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 3A (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.11	N
REVEL	Uncertain	0.30
Sift	Benign	0.083	T
Sift4G	Benign	0.070	T
Polyphen		0.99	D
Vest4		0.53
MutPred		0.31		Loss of MoRF binding (P = 0.0295)
MVP		0.55
MPC		1.3
ClinPred		0.28	T
GERP RS		3.5
PromoterAI		0.032	Neutral
Varity_R		0.19
gMVP		0.39
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.12
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: rs765421231; hg19: chr14-51027016;