19-4896754-C-A

Variant names:

• chr19-4896754-C-A
• NM_001080523.3:c.376G>T

Variant summary

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

The NM_001080523.3(ARRDC5):​c.376G>T​(p.Gly126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ARRDC5 NM_001080523.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

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	c.376G>T	p.Gly126Cys	missense_variant	Exon 2 of 3	ENST00000650722.2	NP_001073992.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRDC5	ENST00000650722.2	c.376G>T	p.Gly126Cys	missense_variant	Exon 2 of 3		NM_001080523.3	ENSP00000498235.1
ARRDC5	ENST00000381781.2	c.418G>T	p.Gly140Cys	missense_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418G>T (p.G140C) alteration is located in exon 2 (coding exon 2) of the ARRDC5 gene. This alteration results from a G to T substitution at nucleotide position 418, causing the glycine (G) at amino acid position 140 to be replaced by a cysteine (C). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0060	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.037	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.58		Loss of MoRF binding (P = 0.1374);
MVP		0.29
MPC		0.53
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.17
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4896766;