rs187822079

chr16-18793379-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015161.3(ARL6IP1):c.494-9T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,472,622 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: ARL6IP1 NM_015161.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008291
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64

Genes affected

ARL6IP1 (HGNC:697): (ADP ribosylation factor like GTPase 6 interacting protein 1) This gene belongs to the ARL6ip family and encodes a transmembrane protein that is predominantly localized to intracytoplasmic membranes. It is highly expressed in early myeloid progenitor cells and thought to be involved in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. Mutations in this gene are associated with spastic paraplegia 61 (SPG61). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-18793379-A-T is Benign according to our data. Variant chr16-18793379-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 541704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARL6IP1	NM_015161.3	c.494-9T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000304414.12
ARL6IP1	NM_001313858.1	c.407-9T>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARL6IP1	ENST00000304414.12	c.494-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_015161.3	P1
ARL6IP1	ENST00000563861.5	c.*76-9T>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
ARL6IP1	ENST00000546206.6	c.407-9T>A		splice_polypyrimidine_tract_variant, intron_variant		2
ARL6IP1	ENST00000562819.5	c.149-9T>A		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 151666 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000665

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000972

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000927 AC: 183 AN: 197432 Hom.: 1 AF XY: 0.000891 AC XY: 96 AN XY: 107720

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.00111 AC: 1463 AN: 1320840 Hom.: 2 Cov.: 21 AF XY: 0.00103 AC XY: 681 AN XY: 661546

Gnomad4 AFR exome AF: 0.00195

Gnomad4 AMR exome AF: 0.000365

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00108 AC: 164 AN: 151782 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74216

Gnomad4 AFR AF: 0.00208

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000665

Gnomad4 NFE AF: 0.000972

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000894 Hom.: 0

Bravo AF: 0.00115

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 61 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

ARL6IP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	7.1
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.030		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: rs187822079; hg19: chr16-18804701;