1-12859760-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_023014.1(PRAMEF2):c.355G>T(p.Ala119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 146,902 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (402 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF2 NM_023014.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.94

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036302805).
• BP6: Variant 1-12859760-G-T is Benign according to our data. Variant chr1-12859760-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3025685.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0115 (1691/146902) while in subpopulation SAS AF= 0.0262 (118/4496). AF 95% confidence interval is 0.0224. There are 19 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRAMEF2	NM_023014.1	c.355G>T	p.Ala119Ser	missense_variant	3/4	ENST00000240189.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRAMEF2	ENST00000240189.2	c.355G>T	p.Ala119Ser	missense_variant	3/4	1	NM_023014.1	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1692 AN: 146804 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.00841

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0142

GnomAD3 exomes AF: 0.000575 AC: 142 AN: 246996 Hom.: 2 AF XY: 0.000591 AC XY: 79 AN XY: 133654

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.000779

Gnomad SAS exome AF: 0.00107

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.000832

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00149 AC: 2123 AN: 1420766 Hom.: 402 Cov.: 60 AF XY: 0.00171 AC XY: 1209 AN XY: 705798

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00468

Gnomad4 SAS exome AF: 0.00586

Gnomad4 FIN exome AF: 0.000762

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.0115 AC: 1691 AN: 146902 Hom.: 19 Cov.: 32 AF XY: 0.0119 AC XY: 852 AN XY: 71716

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0262

Gnomad4 FIN AF: 0.00841

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0146

Alfa AF: 0.0168 Hom.: 11

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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

PRAMEF2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.048
Dann	Benign	0.67
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00052	N
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.017
Sift	Benign	0.40	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.051
MVP		0.048
MPC		0.040
ClinPred		0.0066	T
GERP RS		-1.7
Varity_R		0.048
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201917301; hg19: chr1-12919615; COSMIC: COSV105004891;