chr1-12793292-C-T

Variant names:

• chr1-12793292-C-T
• rs75270454
• NM_023013.4:c.65C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_023013.4(PRAMEF1):​c.65C>T​(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,607,940 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (39 hom.)
• Consequence: PRAMEF1 NM_023013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.754
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026312202).
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

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.65C>T	p.Ala22Val	missense	Exon 2 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.65C>T	p.Ala22Val	missense	Exon 2 of 4	ENSP00000332134.7	O95521

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 81 AN: 150856 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000946

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.000432 AC: 107 AN: 247494 AF XY: 0.000463

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.000715

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000767 AC: 1118 AN: 1456966 Hom.: 39 Cov.: 34 AF XY: 0.000741 AC XY: 537 AN XY: 724702

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

African (AFR) AF: 0.000150 AC: 5 AN: 33396

American (AMR) AF: 0.0000898 AC: 4 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39320

South Asian (SAS) AF: 0.000583 AC: 50 AN: 85724

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4472

European-Non Finnish (NFE) AF: 0.000892 AC: 990 AN: 1109880

Other (OTH) AF: 0.000782 AC: 47 AN: 60136

⚠️ 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 AF: 0.000537 AC: 81 AN: 150974 Hom.: 1 Cov.: 31 AF XY: 0.000380 AC XY: 28 AN XY: 73688

African (AFR) AF: 0.000170 AC: 7 AN: 41284

American (AMR) AF: 0.000265 AC: 4 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4608

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000946 AC: 64 AN: 67656

Other (OTH) AF: 0.00192 AC: 4 AN: 2088

Alfa AF: 0.00939 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000445 AC: 54

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	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.2
DANN	Benign	0.68
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.042	T
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.75
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.060
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.040	D
Polyphen		0.57	P
Vest4		0.11
MVP		0.014
MPC		0.40
ClinPred		0.065	T
GERP RS		-2.0
Varity_R		0.015
gMVP		0.20
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: rs75270454; hg19: chr1-12853441; COSMIC: COSV60009920; COSMIC: COSV60009920;