rs528012262

Variant names:

• chr11-63636199-A-AT
• rs528012262
• NM_015459.5:c.978+7dupA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_015459.5(ATL3):​c.978+7dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,610,820 control chromosomes in the GnomAD database, including 92 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0098 (84 hom.)
• Consequence: ATL3 NM_015459.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.267
• Publications: 1 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 -12 ACMG points.

• BP6: Variant 11-63636199-A-AT is Benign according to our data. Variant chr11-63636199-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1115 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.978+7dupA		splice_region intron	N/A	NP_056274.3
	ATL3	NM_001440716.1		c.927+7dupA		splice_region intron	N/A	NP_001427645.1
	ATL3	NM_001290048.2		c.924+7dupA		splice_region intron	N/A	NP_001276977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	ENST00000398868.8	TSL:1 MANE Select	c.978+7_978+8insA		splice_region intron	N/A	ENSP00000381844.3
	ATL3	ENST00000538786.1	TSL:2	c.924+7_924+8insA		splice_region intron	N/A	ENSP00000437593.1
	ENSG00000256789	ENST00000540307.2	TSL:3	n.121-1292_121-1291insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1116 AN: 152034 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00529

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00631 AC: 1553 AN: 245946 AF XY: 0.00611

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.00202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00534

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00852

GnomAD4 exome AF: 0.00977 AC: 14251 AN: 1458668 Hom.: 84 Cov.: 31 AF XY: 0.00951 AC XY: 6902 AN XY: 725534

African (AFR) AF: 0.00177 AC: 59 AN: 33334

American (AMR) AF: 0.00400 AC: 175 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 55 AN: 25988

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00197 AC: 168 AN: 85384

European-Finnish (FIN) AF: 0.00577 AC: 308 AN: 53396

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.0117 AC: 12994 AN: 1111078

Other (OTH) AF: 0.00811 AC: 489 AN: 60274

GnomAD4 genome AF: 0.00733 AC: 1115 AN: 152152 Hom.: 8 Cov.: 30 AF XY: 0.00667 AC XY: 496 AN XY: 74378

African (AFR) AF: 0.00198 AC: 82 AN: 41488

American (AMR) AF: 0.00648 AC: 99 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4812

European-Finnish (FIN) AF: 0.00529 AC: 56 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 842 AN: 68008

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00948 Hom.: 2

Bravo AF: 0.00682

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00871

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neuropathy, hereditary sensory, type 1F (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27
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: rs528012262; hg19: chr11-63403671;