rs377260429

Variant names:

• chr5-91376727-C-A
• rs377260429
• NM_020801.4:c.404G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-91376727-C-A
• chr5-91376727-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_020801.4(ARRDC3):​c.404G>T​(p.Arg135Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R135H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARRDC3 NM_020801.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 0 publications found

Genes affected

ARRDC3 (HGNC:29263): (arrestin domain containing 3) This gene encodes a member of the arrestin family of proteins, which regulate G protein-mediated signaling. The encoded protein is thought to act as a regulator of breast cancer growth and progression by binding to a phosphorylated form of integrin beta4, a tumor-related antigen, targeting the integrin for internalization and degradation. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a mutagenesis_site Nearly abolishes interaction with ADRB2; when associated with E-56; E-58 and E-153. (size 0) in uniprot entity ARRD3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRDC3	NM_020801.4	c.404G>T	p.Arg135Leu	missense_variant	Exon 3 of 8	ENST00000265138.4	NP_065852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRDC3	ENST00000265138.4	c.404G>T	p.Arg135Leu	missense_variant	Exon 3 of 8	1	NM_020801.4	ENSP00000265138.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.70		Loss of MoRF binding (P = 0.0096);
MVP		0.59
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.83
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs377260429; hg19: chr5-90672544;