1-12859826-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_023014.1(PRAMEF2):c.421A>G(p.Thr141Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T141K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (857 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRAMEF2 NM_023014.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.413

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-12859826-A-G is Benign according to our data. Variant chr1-12859826-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3025331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRAMEF2	NM_023014.1	c.421A>G	p.Thr141Ala	missense_variant	3/4	ENST00000240189.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRAMEF2	ENST00000240189.2	c.421A>G	p.Thr141Ala	missense_variant	3/4	1	NM_023014.1	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1443 AN: 146444 Hom.: 15 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00214

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0131

GnomAD3 exomes AF: 0.000636 AC: 157 AN: 246734 Hom.: 5 AF XY: 0.000585 AC XY: 78 AN XY: 133350

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000988

Gnomad ASJ exome AF: 0.000501

Gnomad EAS exome AF: 0.000834

Gnomad SAS exome AF: 0.000975

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.000999

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00328 AC: 4589 AN: 1397474 Hom.: 857 Cov.: 58 AF XY: 0.00349 AC XY: 2425 AN XY: 693958

Gnomad4 AFR exome AF: 0.000484

Gnomad4 AMR exome AF: 0.00485

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00696

Gnomad4 SAS exome AF: 0.00817

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.00292

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00984 AC: 1442 AN: 146542 Hom.: 15 Cov.: 32 AF XY: 0.00999 AC XY: 714 AN XY: 71466

Gnomad4 AFR AF: 0.00213

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.0134

Alfa AF: 0.0146 Hom.: 11

ExAC AF: 0.00216 AC: 262

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	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.1
Dann	Benign	0.75
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0010	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.056
Sift	Benign	0.30	T
Sift4G	Benign	0.78	T
Polyphen		0.033	B
Vest4		0.069
MVP		0.030
MPC		0.042
ClinPred		0.018	T
GERP RS		-0.97
Varity_R		0.052
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -33

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

Publications

LitVar

Other links and lift over

dbSNP: rs118174776; hg19: chr1-12919681;