14-74949376-G-A

Position:

• chr14-74949376-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000555567.6(PGF):​c.296C>T​(p.Thr99Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000842 in 1,424,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: PGF ENST00000555567.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

PGF (HGNC:8893): (placental growth factor) Enables growth factor activity. Involved in positive regulation of cell population proliferation. Predicted to be located in extracellular region. Predicted to be active in extracellular space. Implicated in several diseases, including brain ischemia; diabetic neuropathy; glioblastoma; myocardial infarction; and pancreatic endocrine carcinoma. Biomarker of several diseases, including artery disease (multiple); autoimmune disease of musculoskeletal system (multiple); epilepsy (multiple); limited scleroderma; and pancreatic endocrine carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

LOC107984690 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3410656).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGF	NM_002632.6	c.296C>T	p.Thr99Met	missense_variant	3/7	ENST00000555567.6	NP_002623.2
LOC107984690	XR_001750826.3	n.5536G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGF	ENST00000555567.6	c.296C>T	p.Thr99Met	missense_variant	3/7	1	NM_002632.6	ENSP00000451040	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000842 AC: 12 AN: 1424742 Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 8 AN XY: 706460

Gnomad4 AFR exome AF: 0.000155

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000493

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.296C>T (p.T99M) alteration is located in exon 3 (coding exon 3) of the PGF gene. This alteration results from a C to T substitution at nucleotide position 296, causing the threonine (T) at amino acid position 99 to be replaced by a methionine (M). 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
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.7	M;M;.;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0, 0.99	.;D;D;D
Vest4		0.39
MutPred		0.38		Gain of catalytic residue at V95 (P = 0.001);Gain of catalytic residue at V95 (P = 0.001);.;Gain of catalytic residue at V95 (P = 0.001);
MVP		0.65
MPC		0.46
ClinPred		0.98	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1011228776; hg19: chr14-75416079; COSMIC: COSV53126169; COSMIC: COSV53126169;