12-6724801-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164094.2(COPS7A):​c.145A>C​(p.Met49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COPS7A NM_001164094.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113159984).

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>C	p.Met49Leu	missense	Exon 2 of 8	NP_001157566.1	Q9UBW8
	COPS7A	NM_001164093.2		c.145A>C	p.Met49Leu	missense	Exon 1 of 7	NP_001157565.1	Q9UBW8
	COPS7A	NM_001164095.3		c.145A>C	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>C	p.Met49Leu	missense	Exon 2 of 8	ENSP00000438115.1	Q9UBW8
	COPS7A	ENST00000229251.7	TSL:1	c.145A>C	p.Met49Leu	missense	Exon 2 of 8	ENSP00000229251.3	Q9UBW8
	COPS7A	ENST00000534947.5	TSL:1	c.145A>C	p.Met49Leu	missense	Exon 1 of 7	ENSP00000446039.1	Q9UBW8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.11	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	0.13
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		0.62	D
GERP RS		6.2
PromoterAI		-0.0040	Neutral
Varity_R		0.55
gMVP		0.15
Mutation Taster		=80/20	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: rs148833801; hg19: chr12-6833967;