NM_015459.5:c.561+6T>G

Variant names:

• chr11-63651930-A-C
• rs893309308
• NM_015459.5:c.561+6T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015459.5(ATL3):​c.561+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,591,396 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ATL3 NM_015459.5 splice_region, intron
• Scores: Splicing: ADA: 0.003646
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• 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, ClinGen, 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	NM_015459.5	MANE Select	c.561+6T>G		splice_region intron	N/A	NP_056274.3
	ATL3	NM_001440716.1		c.510+541T>G		intron	N/A	NP_001427645.1
	ATL3	NM_001290048.2		c.507+6T>G		splice_region intron	N/A	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.561+6T>G		splice_region intron	N/A	ENSP00000381844.3	Q6DD88
	ATL3	ENST00000955365.1		c.558+6T>G		splice_region intron	N/A	ENSP00000625424.1
	ATL3	ENST00000538786.1	TSL:2	c.507+6T>G		splice_region intron	N/A	ENSP00000437593.1	F5H6I7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1439156 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715488

African (AFR) AF: 0.00 AC: 0 AN: 31940

American (AMR) AF: 0.00 AC: 0 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25416

East Asian (EAS) AF: 0.00 AC: 0 AN: 39080

South Asian (SAS) AF: 0.00 AC: 0 AN: 80994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4892

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105868

Other (OTH) AF: 0.00 AC: 0 AN: 59422

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.8
DANN	Benign	0.73
PhyloP100		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0036
dbscSNV1_RF	Benign	0.16
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

Other links and lift over

dbSNP: rs893309308; hg19: chr11-63419402;