rs34261014

Positions:

• chr11-63652563-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_015459.5(ATL3):​c.418C>T​(p.Leu140Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,607,496 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: ATL3 NM_015459.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.44

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]

ENSG00000256789 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-63652563-G-A is Benign according to our data. Variant chr11-63652563-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-63652563-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.44 with no splicing effect.
• BS2: High AC in GnomAd4 at 230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL3	NM_015459.5	c.418C>T	p.Leu140Leu	synonymous_variant	4/13	ENST00000398868.8	NP_056274.3
ATL3	NM_001290048.2	c.364C>T	p.Leu122Leu	synonymous_variant	4/13		NP_001276977.1
ATL3	XM_047426725.1	c.574C>T	p.Leu192Leu	synonymous_variant	5/14		XP_047282681.1
ATL3	XM_006718493.2	c.418C>T	p.Leu140Leu	synonymous_variant	4/12		XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL3	ENST00000398868.8	c.418C>T	p.Leu140Leu	synonymous_variant	4/13	1	NM_015459.5	ENSP00000381844.3
ATL3	ENST00000538786.1	c.364C>T	p.Leu122Leu	synonymous_variant	4/13	2		ENSP00000437593.1
ENSG00000256789	ENST00000540307.1	n.247+1816G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 151962 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00360

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00170 AC: 420 AN: 247240 Hom.: 1 AF XY: 0.00176 AC XY: 236 AN XY: 134194

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000950

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00483

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00191 AC: 2775 AN: 1455416 Hom.: 3 Cov.: 29 AF XY: 0.00185 AC XY: 1341 AN XY: 724220

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00522

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152080 Hom.: 1 Cov.: 32 AF XY: 0.00135 AC XY: 100 AN XY: 74346

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00360

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory, type 1F Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ATL3: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.0
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs34261014; hg19: chr11-63420035;