1-12938878-C-T

Variant names:

• chr1-12938878-C-T
• rs74702454
• NM_001010889.2:c.1228G>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.1228G>A​(p.Val410Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V410L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF6 NM_001010889.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 2 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=0.041336387).

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.1228G>A	p.Val410Met	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.1228G>A	p.Val410Met	missense	Exon 4 of 4	ENSP00000365360.1	Q5VXH4
	PRAMEF6	ENST00000415464.6	TSL:1	c.1228G>A	p.Val410Met	missense	Exon 4 of 4	ENSP00000401281.2	Q5VXH4

Frequencies

GnomAD3 genomes AF: 0.0000546 AC: 8 AN: 146554 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000274

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: 0.0000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 4 AN: 38902 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000316

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000206 AC: 30 AN: 1457528 Hom.: 0 Cov.: 57 AF XY: 0.0000234 AC XY: 17 AN XY: 725052

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33402

American (AMR) AF: 0.000179 AC: 8 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39304

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5044

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1109688

Other (OTH) AF: 0.0000332 AC: 2 AN: 60192

⚠️ 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: 0.0000546 AC: 8 AN: 146554 Hom.: 0 Cov.: 21 AF XY: 0.0000981 AC XY: 7 AN XY: 71382

⚠️ 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: 39496

American (AMR) AF: 0.000274 AC: 4 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4790

South Asian (SAS) AF: 0.00 AC: 0 AN: 4508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000603 AC: 4 AN: 66312

Other (OTH) AF: 0.00 AC: 0 AN: 1986

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.3
DANN	Benign	0.53
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.00049	N
M_CAP	Benign	0.00060	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.31
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.22	B
Vest4		0.031
MutPred		0.33		Gain of ubiquitination at K406 (P = 0.078)
MVP		0.043
MPC		1.7
ClinPred		0.038	T
GERP RS		-2.6
Varity_R		0.026
gMVP		0.17
Mutation Taster		=100/0	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: rs74702454; hg19: chr1-12998708;