20-62303727-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007002.4(ADRM1):c.159C>G(p.Asp53Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,612,366 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: ADRM1 NM_007002.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0123568475).
• BP6: Variant 20-62303727-C-G is Benign according to our data. Variant chr20-62303727-C-G is described in ClinVar as [Benign]. Clinvar id is 722428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRM1	NM_007002.4	c.159C>G	p.Asp53Glu	missense_variant	2/10	ENST00000253003.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRM1	ENST00000253003.7	c.159C>G	p.Asp53Glu	missense_variant	2/10	1	NM_007002.4	P1
ADRM1	ENST00000491935.5	c.159C>G	p.Asp53Glu	missense_variant	3/11	5		P1
ADRM1	ENST00000620230.4	c.159C>G	p.Asp53Glu	missense_variant	2/9	5
ADRM1	ENST00000462554.2	c.159C>G	p.Asp53Glu	missense_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000773 AC: 193 AN: 249810 Hom.: 3 AF XY: 0.000472 AC XY: 64 AN XY: 135470

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1460076 Hom.: 1 Cov.: 31 AF XY: 0.000234 AC XY: 170 AN XY: 726286

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74466

Gnomad4 AFR AF: 0.00912

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.00322

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;.;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.095	N;.;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.14	B;.;B;.
Vest4		0.44
MutPred		0.66		Loss of catalytic residue at D53 (P = 0.1212);Loss of catalytic residue at D53 (P = 0.1212);Loss of catalytic residue at D53 (P = 0.1212);Loss of catalytic residue at D53 (P = 0.1212);
MVP		0.34
MPC		1.3
ClinPred		0.019	T
GERP RS		-0.59
Varity_R		0.33
gMVP		0.42

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: rs115562292; hg19: chr20-60878783;