1-12859763-T-A

Variant names:

• chr1-12859763-T-A
• rs200248611
• NM_023014.1:c.358T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_023014.1(PRAMEF2):​c.358T>A​(p.Trp120Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (430 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF2 NM_023014.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• Publications: 4 publications found

Genes affected

PRAMEF2 (HGNC:28841): (PRAME family member 2) Predicted to be involved in several processes, including negative regulation of apoptotic process; negative regulation of transcription, DNA-templated; and positive regulation of cell population proliferation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060358644).
• BP6: Variant 1-12859763-T-A is Benign according to our data. Variant chr1-12859763-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3025698.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRAMEF2	NM_023014.1	c.358T>A	p.Trp120Arg	missense_variant	Exon 3 of 4	ENST00000240189.2	NP_075390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRAMEF2	ENST00000240189.2	c.358T>A	p.Trp120Arg	missense_variant	Exon 3 of 4	1	NM_023014.1	ENSP00000240189.2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1671 AN: 146716 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.00841

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0147

GnomAD2 exomes AF: 0.000518 AC: 128 AN: 246876 AF XY: 0.000539

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000668

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000410

Gnomad OTH exome AF: 0.000666

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00155 AC: 2195 AN: 1419320 Hom.: 430 Cov.: 58 AF XY: 0.00176 AC XY: 1238 AN XY: 705062

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

African (AFR) AF: 0.000181 AC: 6 AN: 33144

American (AMR) AF: 0.00291 AC: 124 AN: 42606

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 43 AN: 25472

East Asian (EAS) AF: 0.00462 AC: 172 AN: 37198

South Asian (SAS) AF: 0.00591 AC: 480 AN: 81286

European-Finnish (FIN) AF: 0.000667 AC: 35 AN: 52456

Middle Eastern (MID) AF: 0.00249 AC: 10 AN: 4012

European-Non Finnish (NFE) AF: 0.00113 AC: 1224 AN: 1084708

Other (OTH) AF: 0.00173 AC: 101 AN: 58438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0114 AC: 1669 AN: 146812 Hom.: 17 Cov.: 32 AF XY: 0.0116 AC XY: 834 AN XY: 71646

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

African (AFR) AF: 0.00277 AC: 113 AN: 40854

American (AMR) AF: 0.0154 AC: 222 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 44 AN: 3386

East Asian (EAS) AF: 0.0178 AC: 86 AN: 4818

South Asian (SAS) AF: 0.0269 AC: 121 AN: 4506

European-Finnish (FIN) AF: 0.00841 AC: 86 AN: 10220

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.0148 AC: 966 AN: 65458

Other (OTH) AF: 0.0146 AC: 29 AN: 1992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0171 Hom.: 12

ExAC AF: 0.00241 AC: 292

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRAMEF2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.039
DANN	Benign	0.20
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00041	N
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.1	N
PhyloP100		-1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.052
Sift	Benign	0.82	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.027
MutPred		0.45		Gain of loop (P = 0.0166);
MVP		0.076
MPC		0.063
ClinPred		0.020	T
GERP RS		-1.7
Varity_R		0.071
gMVP		0.21
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: rs200248611; hg19: chr1-12919618; COSMIC: COSV105004894;