19-4891378-C-A

Variant names:

• chr19-4891378-C-A
• rs372235175
• NM_001080523.3:c.655G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080523.3(ARRDC5):​c.655G>T​(p.Glu219*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,282 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARRDC5 NM_001080523.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080523.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRDC5	NM_001080523.3	MANE Select	c.655G>T	p.Glu219*	stop_gained	Exon 3 of 3	NP_001073992.2	A0A494BZV3
	ARRDC5	NM_001367189.2		c.721G>T	p.Glu241*	stop_gained	Exon 4 of 4	NP_001354118.1	A0ABB0MV98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRDC5	ENST00000650722.2	MANE Select	c.655G>T	p.Glu219*	stop_gained	Exon 3 of 3	ENSP00000498235.1	A0A494BZV3
	ARRDC5	ENST00000718248.1		c.721G>T	p.Glu241*	stop_gained	Exon 4 of 4	ENSP00000520693.1	A0ABB0MV98
	ARRDC5	ENST00000718249.1		n.*261G>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000520694.1	A0ABB0MV92

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461282 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.017	N
PhyloP100		-2.0
Vest4		0.031
GERP RS		-5.7
Mutation Taster		=80/120	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: rs372235175; hg19: chr19-4891390;