16-18801441-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015161.3(ARL6IP1):c.26C>G(p.Thr9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,612,902 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

ARL6IP1
NM_015161.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.55

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:

ENSG00000260342 (HGNC:):

ENSG00000260342 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05876696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6IP1	NM_015161.3 link	c.26C>G	p.Thr9Ser	missense_variant	Exon 1 of 6	ENST00000304414.12	NP_055976.1	Q15041-1A0A024QYV7
ARL6IP1	NM_001313858.1 link	c.-294C>G		upstream_gene_variant			NP_001300787.1	Q15041-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARL6IP1	ENST00000304414.12 link	c.26C>G	p.Thr9Ser	missense_variant	Exon 1 of 6	1	NM_015161.3	ENSP00000306788.7		Q15041-1
ENSG00000260342	ENST00000567078.2 link	c.26C>G	p.Thr9Ser	missense_variant	Exon 1 of 7	3		ENSP00000454746.2		H3BN98

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000325

AC:

AN:

246082

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133470

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:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.0000631

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1460766

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000774

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 61

Uncertain:1

Mar 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs747185659, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ARL6IP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 583366). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 9 of the ARL6IP1 protein (p.Thr9Ser). -

Inborn genetic diseases

Uncertain:1

May 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26C>G (p.T9S) alteration is located in exon 1 (coding exon 1) of the ARL6IP1 gene. This alteration results from a C to G substitution at nucleotide position 26, causing the threonine (T) at amino acid position 9 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.030

.;T;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.47

T;T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.059

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.29

N;N;N;N

REVEL

Benign

0.057

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.43

T;T;T;.

Polyphen

0.0010

.;B;.;.

Vest4

0.10, 0.16

MutPred

0.23

Loss of catalytic residue at T9 (P = 0.0394);Loss of catalytic residue at T9 (P = 0.0394);Loss of catalytic residue at T9 (P = 0.0394);Loss of catalytic residue at T9 (P = 0.0394);

MVP

0.055

MPC

0.50

ClinPred

0.083

GERP RS

2.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.049

gMVP

0.28

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