Genetic Variant NM_001080523.3:c.775C>A (chr19-4891258-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080523.3(ARRDC5):c.775C>A(p.Leu259Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ARRDC5
NM_001080523.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.58

Publications

4 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080523.3. 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
	ARRDC5	NM_001080523.3	MANE Select	c.775C>A	p.Leu259Met	missense	Exon 3 of 3	NP_001073992.2	A0A494BZV3
	ARRDC5	NM_001367189.2		c.841C>A	p.Leu281Met	missense	Exon 4 of 4	NP_001354118.1	A0ABB0MV98

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARRDC5	ENST00000650722.2	MANE Select	c.775C>A	p.Leu259Met	missense	Exon 3 of 3	ENSP00000498235.1	A0A494BZV3
ARRDC5	ENST00000718248.1		c.841C>A	p.Leu281Met	missense	Exon 4 of 4	ENSP00000520693.1	A0ABB0MV98
ARRDC5	ENST00000718249.1		n.*381C>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000520694.1	A0ABB0MV92

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249146

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111866

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.58

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

2.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.72

REVEL

Benign

0.27

Sift

Uncertain

0.020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MutPred

0.70

Loss of sheet (P = 0.0457)

MVP

0.17

MPC

0.54

ClinPred

0.78

GERP RS

4.9

Varity_R

0.12

gMVP

0.53

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over