19-4891211-G-C

Variant names:

• chr19-4891211-G-C
• rs781568595
• NM_001080523.3:c.822C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080523.3(ARRDC5):​c.822C>G​(p.Ile274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: ARRDC5 NM_001080523.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2849967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARRDC5	NM_001080523.3	c.822C>G	p.Ile274Met	missense_variant	Exon 3 of 3	ENST00000650722.2	NP_001073992.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARRDC5	ENST00000650722.2	c.822C>G	p.Ile274Met	missense_variant	Exon 3 of 3		NM_001080523.3	ENSP00000498235.1
ARRDC5	ENST00000381781.2	c.864C>G	p.Ile288Met	missense_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249200 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.864C>G (p.I288M) alteration is located in exon 3 (coding exon 3) of the ARRDC5 gene. This alteration results from a C to G substitution at nucleotide position 864, causing the isoleucine (I) at amino acid position 288 to be replaced by a methionine (M). 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	Benign	0.095
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.12	B
Vest4		0.35
MutPred		0.70		Gain of disorder (P = 0.0376);
MVP		0.11
MPC		0.47
ClinPred		0.32	T
GERP RS		3.8
Varity_R		0.18
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

Other links and lift over

dbSNP: rs781568595; hg19: chr19-4891223;