Variant 16-18793283-AGTTT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_015161.3(ARL6IP1):c.577_580del(p.Lys193PhefsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ARL6IP1
NM_015161.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.18

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0572 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-18793283-AGTTT-A is Pathogenic according to our data. Variant chr16-18793283-AGTTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101079.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-18793283-AGTTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL6IP1	NM_015161.3 linkuse as main transcript	c.577_580del	p.Lys193PhefsTer37	frameshift_variant	6/6	ENST00000304414.12	NP_055976.1
ARL6IP1	NM_001313858.1 linkuse as main transcript	c.490_493del	p.Lys164PhefsTer37	frameshift_variant	6/6		NP_001300787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL6IP1	ENST00000304414.12 linkuse as main transcript	c.577_580del	p.Lys193PhefsTer37	frameshift_variant	6/6	1	NM_015161.3	ENSP00000306788	P1	Q15041-1
ARL6IP1	ENST00000563861.5 linkuse as main transcript	c.159_162del		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000456596
ARL6IP1	ENST00000546206.6 linkuse as main transcript	c.490_493del	p.Lys164PhefsTer37	frameshift_variant	6/6	2		ENSP00000440048		Q15041-2
ARL6IP1	ENST00000562819.5 linkuse as main transcript	c.232_235del	p.Lys78PhefsTer37	frameshift_variant	3/3	5		ENSP00000457372

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250852

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460232

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 61

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 2014

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2023

Frameshift variant predicted to result in protein extension as the last 11 amino acids are replaced with 36 different amino acids, and no other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28471035, 24482476) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over