9-137613642-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152285.4(ARRDC1):c.308C>T(p.Pro103Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARRDC1 NM_152285.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22765052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARRDC1	NM_152285.4	c.308C>T	p.Pro103Leu	missense_variant	4/8	ENST00000371421.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARRDC1	ENST00000371421.9	c.308C>T	p.Pro103Leu	missense_variant	4/8	1	NM_152285.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.308C>T (p.P103L) alteration is located in exon 4 (coding exon 4) of the ARRDC1 gene. This alteration results from a C to T substitution at nucleotide position 308, causing the proline (P) at amino acid position 103 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.028	T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Benign	0.065
Sift	Benign	0.061	T;T;T
Sift4G	Uncertain	0.012	D;T;T
Polyphen		0.18	B;B;B
Vest4		0.43
MutPred		0.48		Loss of disorder (P = 0.0331);Loss of disorder (P = 0.0331);Loss of disorder (P = 0.0331);
MVP		0.24
MPC		0.14
ClinPred		0.86	D
GERP RS		2.8
Varity_R		0.13
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr9-140508094;