7-94663446-A-G

Variant names:

• chr7-94663446-A-G
• rs1403328984
• ENST00000612748.1:c.118A>G

Variant summary

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

The ENST00000612748.1(PEG10):​c.118A>G​(p.Thr40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEG10 ENST00000612748.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.49
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05093482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEG10	NM_001172437.2	c.118A>G	p.Thr40Ala	missense_variant	Exon 2 of 2		NP_001165908.1
PEG10	NM_001172438.3	c.118A>G	p.Thr40Ala	missense_variant	Exon 2 of 2		NP_001165909.1
PEG10	NM_001184961.1	c.-9A>G		5_prime_UTR_variant	Exon 2 of 2		NP_001171890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEG10	ENST00000612748.1	c.118A>G	p.Thr40Ala	missense_variant	Exon 2 of 3	5		ENSP00000480676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000710 AC: 1 AN: 140778 AF XY: 0.0000134

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383632 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 680346

⚠️ 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: 31292

American (AMR) AF: 0.00 AC: 0 AN: 34924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24292

East Asian (EAS) AF: 0.00 AC: 0 AN: 35558

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069966

Other (OTH) AF: 0.00 AC: 0 AN: 57338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118A>G (p.T40A) alteration is located in exon 2 (coding exon 2) of the PEG10 gene. This alteration results from a A to G substitution at nucleotide position 118, causing the threonine (T) at amino acid position 40 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.15
DANN	Benign	0.58
DEOGEN2	Benign	0.025	T;.
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	0.051	T;T
PhyloP100		-2.5
PrimateAI	Uncertain	0.59	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.046
MVP		0.20
GERP RS		-2.1
gMVP		0.092
Mutation Taster		=299/1	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: rs1403328984; hg19: chr7-94292758;