Variant 19-4891431-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080523.3(ARRDC5):c.602C>T(p.Thr201Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

ARRDC5
NM_001080523.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50

Variant links:

Genes affected

ARRDC5 (HGNC:31407): (arrestin domain containing 5) Predicted to enable ubiquitin ligase-substrate adaptor activity and ubiquitin protein ligase binding activity. Predicted to be involved in protein transport. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARRDC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRDC5	NM_001080523.3 link	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 3	ENST00000650722.2	NP_001073992.2	A6NEK1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRDC5	ENST00000650722.2 link	c.602C>T	p.Thr201Ile	missense_variant	Exon 3 of 3		NM_001080523.3	ENSP00000498235.1		A0A494BZV3
ARRDC5	ENST00000381781.2 link	c.644C>T	p.Thr215Ile	missense_variant	Exon 3 of 3	3				A6NEK1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000433

AC:

107

AN:

246932

Hom.:

AF XY:

0.000380

AC XY:

AN XY:

134232

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000237

Gnomad NFE exome

AF:

0.000855

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000417

AC:

609

AN:

1461202

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

305

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000321

Gnomad4 NFE exome

AF:

0.000499

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000342

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000525

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.000354

AC:

ExAC

AF:

0.000595

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644C>T (p.T215I) alteration is located in exon 3 (coding exon 3) of the ARRDC5 gene. This alteration results from a C to T substitution at nucleotide position 644, causing the threonine (T) at amino acid position 215 to be replaced by an isoleucine (I). 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

Pathogenic

0.84

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.24

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.32

MPC

0.57

ClinPred

0.19

GERP RS

4.9

Varity_R

0.34

gMVP

0.70

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