12-6724801-A-T

Variant names:

• chr12-6724801-A-T
• rs148833801
• NM_001164094.2:c.145A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001164094.2(COPS7A):​c.145A>T​(p.Met49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,614,080 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: COPS7A NM_001164094.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.09
• Publications: 4 publications found

Genes affected

COPS7A (HGNC:16758): (COP9 signalosome subunit 7A) This gene encodes a component of the COP9 signalosome, an evolutionarily conserved multi-subunit protease that regulates the activity of the ubiquitin conjugation pathway. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Mar 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.040943533).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164094.2. 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
	COPS7A	NM_001164094.2	MANE Select	c.145A>T	p.Met49Leu	missense	Exon 2 of 8	NP_001157566.1	Q9UBW8
	COPS7A	NM_001164093.2		c.145A>T	p.Met49Leu	missense	Exon 1 of 7	NP_001157565.1	Q9UBW8
	COPS7A	NM_001164095.3		c.145A>T	p.Met49Leu	missense	Exon 2 of 8	NP_001157567.1	Q9UBW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COPS7A	ENST00000543155.6	TSL:1 MANE Select	c.145A>T	p.Met49Leu	missense	Exon 2 of 8	ENSP00000438115.1	Q9UBW8
	COPS7A	ENST00000229251.7	TSL:1	c.145A>T	p.Met49Leu	missense	Exon 2 of 8	ENSP00000229251.3	Q9UBW8
	COPS7A	ENST00000534947.5	TSL:1	c.145A>T	p.Met49Leu	missense	Exon 1 of 7	ENSP00000446039.1	Q9UBW8

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000467 AC: 117 AN: 250800 AF XY: 0.000553

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000858

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000521 AC: 762 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000506 AC XY: 368 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.000639 AC: 711 AN: 1112006

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74358

African (AFR) AF: 0.000169 AC: 7 AN: 41462

American (AMR) AF: 0.000524 AC: 8 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N
PhyloP100		1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.20
Sift	Benign	0.82	T
Sift4G	Benign	0.61	T
Polyphen		0.0050	B
Vest4		0.17
MutPred		0.48		Gain of catalytic residue at M49 (P = 0.0953)
MVP		0.12
MPC		0.68
ClinPred		0.044	T
GERP RS		6.2
PromoterAI		-0.0085	Neutral
Varity_R		0.55
gMVP		0.15
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148833801; hg19: chr12-6833967;