NM_023013.4:c.349C>T

Variant names:

• chr1-12793976-C-T
• rs141554509
• NM_023013.4:c.349C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023013.4(PRAMEF1):​c.349C>T​(p.Pro117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,608,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PRAMEF1 NM_023013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.61
• Publications: 1 publications found

Genes affected

PRAMEF1 (HGNC:28840): (PRAME family member 1) This gene is a member of the PRAME (preferentially expressed antigen of melanoma) gene family which is expressed in many cancers but may function in reproductive tissues during development. Alternative promoter usage generates two transcript variants, which encode different isoforms. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016624987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023013.4. 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
	PRAMEF1	NM_023013.4	MANE Select	c.349C>T	p.Pro117Ser	missense	Exon 3 of 4	NP_075389.2	O95521

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRAMEF1	ENST00000332296.7	TSL:1 MANE Select	c.349C>T	p.Pro117Ser	missense	Exon 3 of 4	ENSP00000332134.7	O95521

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150846 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250992 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457214 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 724846

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

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.0000449 AC: 2 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39356

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110408

Other (OTH) AF: 0.0000166 AC: 1 AN: 60120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000227980), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150846 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73598

African (AFR) AF: 0.00 AC: 0 AN: 41196

American (AMR) AF: 0.000199 AC: 3 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67538

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000796 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

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	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0030
DANN	Benign	0.078
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.00089	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N
PhyloP100		-3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.047
MVP		0.067
MPC		0.36
ClinPred		0.061	T
GERP RS		-2.6
Varity_R		0.019
gMVP		0.085
Mutation Taster		=99/1	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: rs141554509; hg19: chr1-12854125; COSMIC: COSV60005775; COSMIC: COSV60005775;