20-62308135-C-T

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.971C>T(p.Ala324Val) variant causes a missense change. The variant allele was found at a frequency of 0.012 in 1,609,056 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A324T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 34)
  • Exomes 𝑓: 0.012 (129 hom.)
• Consequence: ADRM1 NM_007002.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.73

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]

LAMA5 (HGNC:6485): (laminin subunit alpha 5) This gene encodes one of the vertebrate laminin alpha chains. Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. The protein encoded by this gene is the alpha-5 subunit of of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523). [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008605361).
• BP6: Variant 20-62308135-C-T is Benign according to our data. Variant chr20-62308135-C-T is described in ClinVar as [Benign]. Clinvar id is 790289.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-62308135-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRM1	NM_007002.4	c.971C>T	p.Ala324Val	missense_variant	8/10	ENST00000253003.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRM1	ENST00000253003.7	c.971C>T	p.Ala324Val	missense_variant	8/10	1	NM_007002.4	P1
ADRM1	ENST00000491935.5	c.971C>T	p.Ala324Val	missense_variant	9/11	5		P1
ADRM1	ENST00000620230.4	c.854C>T	p.Ala285Val	missense_variant	7/9	5
LAMA5	ENST00000492698.1	n.714G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1330 AN: 152224 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00822 AC: 2017 AN: 245264 Hom.: 7 AF XY: 0.00844 AC XY: 1126 AN XY: 133404

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00583

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00706

Gnomad FIN exome AF: 0.00294

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.0123 AC: 17903 AN: 1456714 Hom.: 129 Cov.: 35 AF XY: 0.0122 AC XY: 8820 AN XY: 724692

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00783

Gnomad4 FIN exome AF: 0.00396

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00872 AC: 1328 AN: 152342 Hom.: 11 Cov.: 34 AF XY: 0.00797 AC XY: 594 AN XY: 74494

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00329

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0121 Hom.: 10

Bravo AF: 0.00858

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0132 AC: 113

ExAC AF: 0.00822 AC: 992

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0125

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

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.41
MVP		0.43
MPC		0.11
ClinPred		0.034	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.40

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: rs45576934; hg19: chr20-60883191; COSMIC: COSV53363394; COSMIC: COSV53363394;