20-62303727-C-A

Variant names:

• chr20-62303727-C-A
• rs115562292
• NM_007002.4:c.159C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007002.4(ADRM1):​c.159C>A​(p.Asp53Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADRM1 NM_007002.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165
• Publications: 0 publications found

Genes affected

ADRM1 (HGNC:15759): (ADRM1 26S proteasome ubiquitin receptor) This gene encodes a member of the adhesion regulating molecule 1 protein family. The encoded protein is a component of the proteasome where it acts as a ubiquitin receptor and recruits the deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L5. Increased levels of the encoded protein are associated with increased cell adhesion, which is likely an indirect effect of this intracellular protein. Dysregulation of this gene has been implicated in carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2778522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007002.4. 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
	ADRM1	NM_007002.4	MANE Select	c.159C>A	p.Asp53Glu	missense	Exon 2 of 10	NP_008933.2
	ADRM1	NM_175573.2		c.159C>A	p.Asp53Glu	missense	Exon 2 of 10	NP_783163.1	Q16186
	ADRM1	NM_001281437.1		c.159C>A	p.Asp53Glu	missense	Exon 2 of 9	NP_001268366.1	Q16186

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRM1	ENST00000253003.7	TSL:1 MANE Select	c.159C>A	p.Asp53Glu	missense	Exon 2 of 10	ENSP00000253003.2	Q16186
	ADRM1	ENST00000906321.1		c.159C>A	p.Asp53Glu	missense	Exon 2 of 10	ENSP00000576380.1
	ADRM1	ENST00000906322.1		c.159C>A	p.Asp53Glu	missense	Exon 2 of 10	ENSP00000576381.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460078 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726286

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.095	N
PhyloP100		-0.17
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.075
Sift	Benign	0.34	T
Sift4G	Benign	0.38	T
Polyphen		0.14	B
Vest4		0.44
MutPred		0.66		Loss of catalytic residue at D53 (P = 0.1212)
MVP		0.34
MPC		1.3
ClinPred		0.53	D
GERP RS		-0.59
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.42
Mutation Taster		=87/13	polymorphism

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: rs115562292; hg19: chr20-60878783;