rs200747906

Positions:

• chr11-63643503-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015459.5(ATL3):​c.712-8A>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 0.000503 in 1,602,972 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: ATL3 NM_015459.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001826
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.65

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:58146):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 11-63643503-T-C is Benign according to our data. Variant chr11-63643503-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL3	NM_015459.5	c.712-8A>G		splice_region_variant, intron_variant		ENST00000398868.8	NP_056274.3
ATL3	NM_001290048.2	c.658-8A>G		splice_region_variant, intron_variant			NP_001276977.1
ATL3	XM_047426725.1	c.868-8A>G		splice_region_variant, intron_variant			XP_047282681.1
ATL3	XM_006718493.2	c.655-8A>G		splice_region_variant, intron_variant			XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL3	ENST00000398868.8	c.712-8A>G		splice_region_variant, intron_variant		1	NM_015459.5	ENSP00000381844.3
ATL3	ENST00000538786.1	c.658-8A>G		splice_region_variant, intron_variant		2		ENSP00000437593.1
ENSG00000256789	ENST00000540307.1	n.59+5768T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000689 AC: 165 AN: 239368 Hom.: 1 AF XY: 0.000623 AC XY: 81 AN XY: 130108

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000470

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000246

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000869

GnomAD4 exome AF: 0.000508 AC: 737 AN: 1450688 Hom.: 3 Cov.: 30 AF XY: 0.000488 AC XY: 352 AN XY: 721024

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.000394

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000750

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74482

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000480

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 22, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.57
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0040
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: rs200747906; hg19: chr11-63410975;