chr11-63646550-T-C

Variant names:

• chr11-63646550-T-C
• rs587777108
• NM_015459.5:c.575A>G
• ATL3 p.Tyr192Cys

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015459.5(ATL3):​c.575A>G​(p.Tyr192Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y192Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.97
• Publications: 24 publications found

Genes affected

ATL3 (HGNC:24526): (atlastin GTPase 3) This gene encodes a member of a family of dynamin-like, integral membrane GTPases. The encoded protein is required for the proper formation of the network of interconnected tubules of the endoplasmic reticulum. Mutations in this gene may be associated with hereditary sensory neuropathy type IF. Alternatively spliced transcript variants that encode distinct isoforms have been described. [provided by RefSeq, Feb 2014]

ATL3 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory, type 1F

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LNCROPM (HGNC:58146):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-63646550-T-C is Pathogenic according to our data. Variant chr11-63646550-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97070.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015459.5. 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
	ATL3	NM_015459.5	MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 13	NP_056274.3
	ATL3	NM_001440716.1		c.524A>G	p.Tyr175Cys	missense	Exon 5 of 12	NP_001427645.1
	ATL3	NM_001290048.2		c.521A>G	p.Tyr174Cys	missense	Exon 6 of 13	NP_001276977.1	F5H6I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	ENST00000398868.8	TSL:1 MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 13	ENSP00000381844.3	Q6DD88
	ATL3	ENST00000955365.1		c.572A>G	p.Tyr191Cys	missense	Exon 6 of 13	ENSP00000625424.1
	ATL3	ENST00000538786.1	TSL:2	c.521A>G	p.Tyr174Cys	missense	Exon 6 of 13	ENSP00000437593.1	F5H6I7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neuropathy, hereditary sensory, type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.94
gMVP		0.74
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587777108;

hg19: chr11-63414022;