1-12938685-C-T

Variant names:

• chr1-12938685-C-T
• rs575897136
• NM_001010889.2:c.1421G>A

Variant summary

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

The NM_001010889.2(PRAMEF6):​c.1421G>A​(p.Cys474Tyr) 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 0.0016 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF6 NM_001010889.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.157
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014971614).

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.1421G>A	p.Cys474Tyr	missense	Exon 4 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.1421G>A	p.Cys474Tyr	missense	Exon 4 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.1421G>A	p.Cys474Tyr	missense	Exon 4 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 233 AN: 143036 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000490

Gnomad ASJ AF: 0.000587

Gnomad EAS AF: 0.000861

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.0000450

Gnomad OTH AF: 0.000511

GnomAD2 exomes AF: 0.000179 AC: 6 AN: 33582 AF XY: 0.000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000964

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000304 AC: 442 AN: 1454426 Hom.: 0 Cov.: 30 AF XY: 0.000275 AC XY: 199 AN XY: 723710

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

African (AFR) AF: 0.00713 AC: 237 AN: 33250

American (AMR) AF: 0.000807 AC: 36 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.000384 AC: 10 AN: 26064

East Asian (EAS) AF: 0.000508 AC: 20 AN: 39380

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85792

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5176

European-Non Finnish (NFE) AF: 0.0000913 AC: 101 AN: 1106704

Other (OTH) AF: 0.000549 AC: 33 AN: 60058

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00163 AC: 234 AN: 143142 Hom.: 0 Cov.: 20 AF XY: 0.00155 AC XY: 108 AN XY: 69696

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

African (AFR) AF: 0.00591 AC: 215 AN: 36392

American (AMR) AF: 0.000489 AC: 7 AN: 14312

Ashkenazi Jewish (ASJ) AF: 0.000587 AC: 2 AN: 3410

East Asian (EAS) AF: 0.000863 AC: 4 AN: 4636

South Asian (SAS) AF: 0.000226 AC: 1 AN: 4420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10162

Middle Eastern (MID) AF: 0.00362 AC: 1 AN: 276

European-Non Finnish (NFE) AF: 0.0000450 AC: 3 AN: 66650

Other (OTH) AF: 0.000505 AC: 1 AN: 1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00236 Hom.: 0

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	0.087
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.0
DANN	Benign	0.30
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0011	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.16
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.0060
Sift	Benign	0.071	T
Sift4G	Benign	0.063	T
Polyphen		0.0020	B
Vest4		0.053
MutPred		0.60		Gain of solvent accessibility (P = 0.0202)
MVP		0.043
MPC		2.4
ClinPred		0.016	T
GERP RS		-0.93
Varity_R		0.064
gMVP		0.26
Mutation Taster		=100/0	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: rs575897136; hg19: chr1-12998515; COSMIC: COSV61910461;