chr1-12941141-C-T

Variant names:

• chr1-12941141-C-T
• rs761497343
• NM_001010889.2:c.712G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001010889.2(PRAMEF6):​c.712G>A​(p.Val238Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 2)
  • Exomes 𝑓: 0.00022 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF6 NM_001010889.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.88
• Publications: 0 publications found

Genes affected

PRAMEF6 (HGNC:30583): (PRAME family member 6) Enables ubiquitin ligase-substrate adaptor activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07561666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010889.2. 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
	PRAMEF6	NM_001010889.2	MANE Select	c.712G>A	p.Val238Ile	missense	Exon 3 of 4	NP_001010889.1	Q5VXH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRAMEF6	ENST00000376189.5	TSL:1 MANE Select	c.712G>A	p.Val238Ile	missense	Exon 3 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.712G>A	p.Val238Ile	missense	Exon 3 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 3 AN: 10134 Hom.: 0 Cov.: 2

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000812

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: 0.000350

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000980 AC: 5 AN: 51004 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: 0.000240

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000224 AC: 87 AN: 388816 Hom.: 3 Cov.: 3 AF XY: 0.000202 AC XY: 41 AN XY: 203418

African (AFR) AF: 0.000381 AC: 3 AN: 7868

American (AMR) AF: 0.0000589 AC: 1 AN: 16986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11466

East Asian (EAS) AF: 0.000185 AC: 5 AN: 26994

South Asian (SAS) AF: 0.00 AC: 0 AN: 37228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1540

European-Non Finnish (NFE) AF: 0.000301 AC: 72 AN: 239346

Other (OTH) AF: 0.000272 AC: 6 AN: 22060

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000296 AC: 3 AN: 10134 Hom.: 0 Cov.: 2 AF XY: 0.000220 AC XY: 1 AN XY: 4548

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 760

American (AMR) AF: 0.000812 AC: 1 AN: 1232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 296

East Asian (EAS) AF: 0.00 AC: 0 AN: 572

South Asian (SAS) AF: 0.00 AC: 0 AN: 280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.000350 AC: 2 AN: 5716

Other (OTH) AF: 0.00 AC: 0 AN: 122

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000509044), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

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	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.075
DANN	Benign	0.40
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.00038	N
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-3.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.018
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.047
MutPred		0.27		Loss of catalytic residue at V238 (P = 0.0226)
MVP		0.043
MPC		1.4
ClinPred		0.052	T
GERP RS		-3.1
Varity_R		0.017
gMVP		0.12
Mutation Taster		=97/3	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: rs761497343; hg19: chr1-13000971;