ENST00000612748.1:c.215C>T

Variant names:

• chr7-94663543-C-T
• rs1296215995
• ENST00000612748.1:c.215C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000612748.1(PEG10):​c.215C>T​(p.Ala72Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,552,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: PEG10 ENST00000612748.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 1 publications found

Genes affected

PEG10 (HGNC:14005): (paternally expressed 10) This is a paternally expressed imprinted gene that is thought to have been derived from the Ty3/Gypsy family of retrotransposons. It contains two overlapping open reading frames, RF1 and RF2, and expresses two proteins: a shorter, gag-like protein (with a CCHC-type zinc finger domain) from RF1; and a longer, gag/pol-like fusion protein (with an additional aspartic protease motif) from RF1/RF2 by -1 translational frameshifting (-1 FS). While -1 FS has been observed in RNA viruses and transposons in both prokaryotes and eukaryotes, this gene represents the first example of -1 FS in a eukaryotic cellular gene. This gene is highly conserved across mammalian species and retains the heptanucleotide (GGGAAAC) and pseudoknot elements required for -1 FS. It is expressed in adult and embryonic tissues (most notably in placenta) and reported to have a role in cell proliferation, differentiation and apoptosis. Overexpression of this gene has been associated with several malignancies, such as hepatocellular carcinoma and B-cell lymphocytic leukemia. Knockout mice lacking this gene showed early embryonic lethality with placental defects, indicating the importance of this gene in embryonic development. Additional isoforms resulting from alternatively spliced transcript variants, and use of upstream non-AUG (CUG) start codon have been reported for this gene. [provided by RefSeq, Oct 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06875023).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000612748.1. 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
	PEG10	NM_001172437.2		c.215C>T	p.Ala72Val	missense	Exon 2 of 2	NP_001165908.1	Q86TG7-4
	PEG10	NM_001184961.1		c.89C>T	p.Ala30Val	missense	Exon 2 of 2	NP_001171890.1	Q86TG7
	PEG10	NM_001172438.3		c.215C>T	p.Ala72Val	missense	Exon 2 of 2	NP_001165909.1	Q86TG7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEG10	ENST00000612748.1	TSL:5	c.215C>T	p.Ala72Val	missense	Exon 2 of 3	ENSP00000480676.1	A0A087WX23
	PEG10	ENST00000615790.5	TSL:1	c.89C>T	p.Ala30Val	missense	Exon 2 of 2	ENSP00000482653.2	Q86TG7-3
	PEG10	ENST00000482108.1	TSL:1	c.-14C>T		5_prime_UTR	Exon 2 of 2	ENSP00000417587.1	Q86TG7-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000126 AC: 2 AN: 158350 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000714 AC: 10 AN: 1400150 Hom.: 0 Cov.: 35 AF XY: 0.00000579 AC XY: 4 AN XY: 690658

African (AFR) AF: 0.00 AC: 0 AN: 31608

American (AMR) AF: 0.0000280 AC: 1 AN: 35722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35750

South Asian (SAS) AF: 0.00 AC: 0 AN: 79240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1079370

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74192

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

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	0.073
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.49
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.069	T
PhyloP100		1.4
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.082	B
Vest4		0.061
MVP		0.27
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.058
Mutation Taster		=300/0	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: rs1296215995; hg19: chr7-94292855; COSMIC: COSV101509837; COSMIC: COSV101509837;