9-111371725-T-C

Variant names:

• chr9-111371725-T-C
• rs1433761253
• NM_001364929.1:c.4633A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001364929.1(ECPAS):​c.4633A>G​(p.Met1545Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1545T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ECPAS NM_001364929.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

Genes affected

ECPAS (HGNC:29020): (Ecm29 proteasome adaptor and scaffold) Enables proteasome binding activity. Involved in ubiquitin-dependent ERAD pathway. Located in several cellular components, including centrosome; cytoplasmic vesicle; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22867778).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364929.1. 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
	ECPAS	NM_001364929.1	MANE Select	c.4633A>G	p.Met1545Val	missense	Exon 43 of 50	NP_001351858.1	Q5VYK3-2
	ECPAS	NM_001364931.1		c.4651A>G	p.Met1551Val	missense	Exon 42 of 49	NP_001351860.1	Q5VYK3-1
	ECPAS	NM_001363756.2		c.4633A>G	p.Met1545Val	missense	Exon 42 of 49	NP_001350685.1	A0AAA9X0G7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECPAS	ENST00000684092.1	MANE Select	c.4633A>G	p.Met1545Val	missense	Exon 43 of 50	ENSP00000507419.1	Q5VYK3-2
	ECPAS	ENST00000259335.8	TSL:1	c.5167A>G	p.Met1723Val	missense	Exon 44 of 51	ENSP00000259335.4	J3KN16
	ECPAS	ENST00000338205.9	TSL:5	c.4633A>G	p.Met1545Val	missense	Exon 42 of 49	ENSP00000339889.5	A0AAA9X0G7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248944 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461390 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111596

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.084
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.91	T
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Vest4		0.61
MutPred		0.45		Loss of disorder (P = 0.0956)
MVP		0.80
MPC		0.17
ClinPred		0.24	T
GERP RS		5.7
PromoterAI		0.028	Neutral
gMVP		0.59
Mutation Taster		=59/41	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: rs1433761253; hg19: chr9-114134005;