rs189119869

Positions:

• chr11-63631145-T-C
• chr11-63631145-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015459.5(ATL3):​c.1434A>G​(p.Gly478=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,614,170 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (32 hom.)
• Consequence: ATL3 NM_015459.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.14

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-63631145-T-C is Benign according to our data. Variant chr11-63631145-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-63631145-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS2: High AC in GnomAd4 at 656 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL3	NM_015459.5	c.1434A>G	p.Gly478=	synonymous_variant	12/13	ENST00000398868.8
ATL3	NM_001290048.2	c.1380A>G	p.Gly460=	synonymous_variant	12/13
ATL3	XM_047426725.1	c.1590A>G	p.Gly530=	synonymous_variant	13/14
ATL3	XM_006718493.2	c.1377A>G	p.Gly459=	synonymous_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL3	ENST00000398868.8	c.1434A>G	p.Gly478=	synonymous_variant	12/13	1	NM_015459.5
ATL3	ENST00000538786.1	c.1380A>G	p.Gly460=	synonymous_variant	12/13	2		P1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152160 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00475 AC: 1185 AN: 249524 Hom.: 10 AF XY: 0.00442 AC XY: 599 AN XY: 135370

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00357 AC: 5223 AN: 1461892 Hom.: 32 Cov.: 32 AF XY: 0.00360 AC XY: 2616 AN XY: 727246

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.00350

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152278 Hom.: 6 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00421 Hom.: 1

Bravo AF: 0.00229

EpiCase AF: 0.00403

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATL3: BP4, BP7, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Neuropathy, hereditary sensory, type 1F Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.71
DANN	Benign	0.59

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: rs189119869; hg19: chr11-63398617; COSMIC: COSV100219755; COSMIC: COSV100219755;