Genetic Variant ARL6IP1:p.Thr9Asn (chr16-18801441-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015161.3(ARL6IP1):c.26C>A(p.Thr9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ARL6IP1
NM_015161.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

Publications

0 publications found

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 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

ARL6IP1 links:

ENSG00000260342 (HGNC:):

ENSG00000260342 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.101576895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARL6IP1	NM_015161.3 link	c.26C>A	p.Thr9Asn	missense_variant	Exon 1 of 6	ENST00000304414.12	NP_055976.1	Q15041-1A0A024QYV7
ARL6IP1	NM_001313858.1 link	c.-294C>A		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>A	p.Thr9Asn	missense_variant	Exon 1 of 6	1	NM_015161.3	ENSP00000306788.7		Q15041-1
ENSG00000260342	ENST00000567078.2 link	c.26C>A	p.Thr9Asn	missense_variant	Exon 1 of 7	3		ENSP00000454746.2		H3BN98

Frequencies

GnomAD3 genomes

AF:

0.00000657

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.052

.;T;.;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

T;T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;.;.

PhyloP100

1.6

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.71

N;N;N;N

REVEL

Benign

0.022

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Benign

0.088

T;T;T;.

Polyphen

0.022

.;B;.;.

Vest4

0.25, 0.37

MutPred

0.21

Loss of phosphorylation at T9 (P = 0.0402);Loss of phosphorylation at T9 (P = 0.0402);Loss of phosphorylation at T9 (P = 0.0402);Loss of phosphorylation at T9 (P = 0.0402);

MVP

0.085

MPC

0.64

ClinPred

0.46

GERP RS

2.5

PromoterAI

0.030

Neutral

(source)

Varity_R

0.11

gMVP

0.50

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over