dbSNP rs774721041: ARRDC1:p.Pro37Gln (chr9-137605827-C-A) – 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_152285.4(ARRDC1):c.110C>A(p.Pro37Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 1,106,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P37L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

ARRDC1
NM_152285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.980

Publications

0 publications found

Variant links:

Genes affected

ARRDC1 (HGNC:28633): (arrestin domain containing 1) Enables several functions, including arrestin family protein binding activity; ubiquitin ligase-substrate adaptor activity; and ubiquitin protein ligase binding activity. Involved in several processes, including cellular protein metabolic process; extracellular vesicle biogenesis; and negative regulation of Notch signaling pathway. Located in cytoplasmic vesicle; extracellular vesicle; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARRDC1 links:

ENSG00000283411 (HGNC:):

ENSG00000283411 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=0.14711362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRDC1	NM_152285.4 link	c.110C>A	p.Pro37Gln	missense_variant	Exon 1 of 8	ENST00000371421.9	NP_689498.1	Q8N5I2
ARRDC1	NM_001317968.2 link	c.110C>A	p.Pro37Gln	missense_variant	Exon 1 of 7		NP_001304897.1
ARRDC1	XM_005266119.2 link	c.110C>A	p.Pro37Gln	missense_variant	Exon 1 of 7		XP_005266176.1
ARRDC1	XM_047424069.1 link	c.110C>A	p.Pro37Gln	missense_variant	Exon 1 of 8		XP_047280025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRDC1	ENST00000371421.9 link	c.110C>A	p.Pro37Gln	missense_variant	Exon 1 of 8	1	NM_152285.4	ENSP00000360475.4		Q8N5I2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

7538

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000813

AC:

AN:

1106886

Hom.:

Cov.:

AF XY:

0.00000942

AC XY:

AN XY:

530520

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000444

AC:

AN:

22508

American (AMR)

AF:

0.00

AC:

AN:

8390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14328

East Asian (EAS)

AF:

0.00

AC:

AN:

25488

South Asian (SAS)

AF:

0.00

AC:

AN:

32834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24258

Middle Eastern (MID)

AF:

0.000334

AC:

AN:

2990

European-Non Finnish (NFE)

AF:

0.00000751

AC:

AN:

932390

Other (OTH)

AF:

0.00

AC:

AN:

43700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0010

T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.60

T;T;T

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.49

N;.;.

PhyloP100

0.98

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.76

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.46

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.025

B;B;B

Vest4

0.20

MutPred

0.41

Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);

MVP

0.32

MPC

0.12

ClinPred

0.20

GERP RS

4.2

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.12

gMVP

0.29

Mutation Taster

=80/20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over