11-63644219-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015459.5(ATL3):c.661T>A(p.Tyr221Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y221D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35637587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL3	NM_015459.5	c.661T>A	p.Tyr221Asn	missense_variant	7/13	ENST00000398868.8
ATL3	NM_001290048.2	c.607T>A	p.Tyr203Asn	missense_variant	7/13
ATL3	XM_047426725.1	c.817T>A	p.Tyr273Asn	missense_variant	8/14
ATL3	XM_006718493.2	c.604T>A	p.Tyr202Asn	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL3	ENST00000398868.8	c.661T>A	p.Tyr221Asn	missense_variant	7/13	1	NM_015459.5
	ENST00000540307.1	n.60-6341A>T		intron_variant, non_coding_transcript_variant		3
ATL3	ENST00000538786.1	c.607T>A	p.Tyr203Asn	missense_variant	7/13	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.25
Sift	Benign	0.10	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.62	P;.
Vest4		0.47
MutPred		0.54		Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.68
MPC		1.3
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.53
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045392653; hg19: chr11-63411691;