rs753546335

Variant names:

• chr11-63631455-T-G
• rs753546335
• NM_015459.5:c.1124A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015459.5(ATL3):​c.1124A>C​(p.Lys375Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,454,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256789 (HGNC:58146):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18913761).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	NM_015459.5	MANE Select	c.1124A>C	p.Lys375Thr	missense	Exon 12 of 13	NP_056274.3
	ATL3	NM_001440716.1		c.1073A>C	p.Lys358Thr	missense	Exon 11 of 12	NP_001427645.1
	ATL3	NM_001290048.2		c.1070A>C	p.Lys357Thr	missense	Exon 12 of 13	NP_001276977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	ENST00000398868.8	TSL:1 MANE Select	c.1124A>C	p.Lys375Thr	missense	Exon 12 of 13	ENSP00000381844.3
	ATL3	ENST00000538786.1	TSL:2	c.1070A>C	p.Lys357Thr	missense	Exon 12 of 13	ENSP00000437593.1
	ENSG00000256789	ENST00000540307.2	TSL:3	n.121-6036T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1454472 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 722692

African (AFR) AF: 0.00 AC: 0 AN: 33036

American (AMR) AF: 0.00 AC: 0 AN: 43560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.0000253 AC: 28 AN: 1108122

Other (OTH) AF: 0.0000166 AC: 1 AN: 60066

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.084
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.0080	B
Vest4		0.45
MutPred		0.36		Loss of ubiquitination at K375 (P = 0.0067)
MVP		0.15
MPC		0.62
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.60
gMVP		0.29
Mutation Taster		=68/32	polymorphism

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: rs753546335; hg19: chr11-63398927;