NM_015161.3:c.494-62dupA

Variant names:

• chr16-18793431-C-CT
• rs34143424
• NM_015161.3:c.494-62dupA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_015161.3(ARL6IP1):​c.494-62dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 605,932 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 0)
  • Exomes 𝑓: 0.045 (0 hom.)
• Consequence: ARL6IP1 NM_015161.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.236
• Publications: 2 publications found

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]

ARL6IP1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 61

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000260342 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 16-18793431-C-CT is Benign according to our data. Variant chr16-18793431-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 1300711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015161.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6IP1	NM_015161.3	MANE Select	c.494-62dupA		intron	N/A	NP_055976.1	Q15041-1
	ARL6IP1	NM_001313858.1		c.407-62dupA		intron	N/A	NP_001300787.1	Q15041-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL6IP1	ENST00000304414.12	TSL:1 MANE Select	c.494-62_494-61insA		intron	N/A	ENSP00000306788.7	Q15041-1
	ENSG00000260342	ENST00000567078.2	TSL:3	c.493+1167_493+1168insA		intron	N/A	ENSP00000454746.2	H3BN98
	ARL6IP1	ENST00000563861.5	TSL:1	n.*76-62_*76-61insA		intron	N/A	ENSP00000456596.1	H3BS91

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 724 AN: 140098 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00228

Gnomad ASJ AF: 0.000598

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.000910

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00420

GnomAD4 exome AF: 0.0446 AC: 20758 AN: 465850 Hom.: 0 AF XY: 0.0444 AC XY: 10771 AN XY: 242406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0613 AC: 631 AN: 10290

American (AMR) AF: 0.0475 AC: 539 AN: 11356

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 414 AN: 10420

East Asian (EAS) AF: 0.0660 AC: 1444 AN: 21892

South Asian (SAS) AF: 0.0418 AC: 1471 AN: 35230

European-Finnish (FIN) AF: 0.0320 AC: 895 AN: 27962

Middle Eastern (MID) AF: 0.0436 AC: 75 AN: 1720

European-Non Finnish (NFE) AF: 0.0440 AC: 14275 AN: 324140

Other (OTH) AF: 0.0444 AC: 1014 AN: 22840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00518 AC: 726 AN: 140082 Hom.: 7 Cov.: 0 AF XY: 0.00496 AC XY: 335 AN XY: 67494

African (AFR) AF: 0.0157 AC: 601 AN: 38250

American (AMR) AF: 0.00228 AC: 32 AN: 14028

Ashkenazi Jewish (ASJ) AF: 0.000598 AC: 2 AN: 3344

East Asian (EAS) AF: 0.00103 AC: 5 AN: 4848

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4412

European-Finnish (FIN) AF: 0.000910 AC: 7 AN: 7696

Middle Eastern (MID) AF: 0.00373 AC: 1 AN: 268

European-Non Finnish (NFE) AF: 0.00101 AC: 65 AN: 64438

Other (OTH) AF: 0.00419 AC: 8 AN: 1910

Alfa AF: 0.000314 Hom.: 222

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24
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: rs34143424; hg19: chr16-18804753;