11-63631145-T-C

Variant names:

• chr11-63631145-T-C
• rs189119869
• NM_015459.5:c.1434A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015459.5(ATL3):​c.1434A>G​(p.Gly478Gly) 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
• Publications: 2 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 474834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS2: High AC in GnomAd4 at 656 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.1434A>G	p.Gly478Gly	synonymous	Exon 12 of 13	NP_056274.3
	ATL3	NM_001440716.1		c.1383A>G	p.Gly461Gly	synonymous	Exon 11 of 12	NP_001427645.1
	ATL3	NM_001290048.2		c.1380A>G	p.Gly460Gly	synonymous	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.1434A>G	p.Gly478Gly	synonymous	Exon 12 of 13	ENSP00000381844.3
	ATL3	ENST00000538786.1	TSL:2	c.1380A>G	p.Gly460Gly	synonymous	Exon 12 of 13	ENSP00000437593.1
	ENSG00000256789	ENST00000540307.2	TSL:3	n.121-6346T>C		intron	N/A

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

GnomAD2 exomes AF: 0.00475 AC: 1185 AN: 249524 AF XY: 0.00442

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.0211 AC: 1127 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00350 AC: 3895 AN: 1112010

Other (OTH) AF: 0.00240 AC: 145 AN: 60396

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

African (AFR) AF: 0.000433 AC: 18 AN: 41552

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00537 AC: 365 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00421 Hom.: 1

Bravo AF: 0.00229

EpiCase AF: 0.00403

EpiControl AF: 0.00320

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Neuropathy, hereditary sensory, type 1F (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.71
DANN	Benign	0.59
PhyloP100		-4.1
Mutation Taster		=100/0	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: rs189119869; hg19: chr11-63398617; COSMIC: COSV100219755; COSMIC: COSV100219755;