14-50621837-T-G

Variant names:

• chr14-50621837-T-G
• rs192428744
• NM_015915.5:c.991-6T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015915.5(ATL1):​c.991-6T>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 0.000137 in 1,557,344 control chromosomes in the GnomAD database, including 2 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 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: ATL1 NM_015915.5 splice_region, intron
• Scores: Splicing: ADA: 0.0006110
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0310

Genes affected

ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-50621837-T-G is Benign according to our data. Variant chr14-50621837-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 313303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00019 (29/152310) while in subpopulation EAS AF = 0.00347 (18/5190). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 SD,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.991-6T>G		splice_region_variant, intron_variant	Intron 9 of 13	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.991-6T>G		splice_region_variant, intron_variant	Intron 10 of 13		NP_001121185.1
ATL1	NM_181598.4	c.991-6T>G		splice_region_variant, intron_variant	Intron 9 of 12		NP_853629.2
ATL1	XM_047431430.1	c.991-6T>G		splice_region_variant, intron_variant	Intron 10 of 14		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.991-6T>G		splice_region_variant, intron_variant	Intron 9 of 13	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000429 AC: 103 AN: 240280 AF XY: 0.000392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00326

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.0000744

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000132 AC: 185 AN: 1405034 Hom.: 2 Cov.: 27 AF XY: 0.000125 AC XY: 88 AN XY: 701428

African (AFR) AF: 0.00 AC: 0 AN: 32242

American (AMR) AF: 0.00 AC: 0 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25404

East Asian (EAS) AF: 0.00226 AC: 89 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 84124

European-Finnish (FIN) AF: 0.00121 AC: 64 AN: 52930

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5436

European-Non Finnish (NFE) AF: 0.0000160 AC: 17 AN: 1062934

Other (OTH) AF: 0.000240 AC: 14 AN: 58444

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000576 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 3A Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neuropathy, hereditary sensory, type 1D Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Aug 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00061
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs192428744; hg19: chr14-51088555; COSMIC: COSV105915479;