NM_016205.3:c.1016G>A

Variant names:

• chr4-156763112-C-T
• NM_016205.3:c.1016G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016205.3(PDGFC):​c.1016G>A​(p.Cys339Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDGFC NM_016205.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

PDGFC (HGNC:8801): (platelet derived growth factor C) The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a core motif of eight cysteines. This gene product appears to form only homodimers. It differs from the platelet-derived growth factor alpha and beta polypeptides in having an unusual N-terminal domain, the CUB domain. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016205.3. 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
	PDGFC	NM_016205.3	MANE Select	c.1016G>A	p.Cys339Tyr	missense	Exon 6 of 6	NP_057289.1	Q9NRA1-1
	PDGFC	NR_036641.2		n.1973G>A		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFC	ENST00000502773.6	TSL:1 MANE Select	c.1016G>A	p.Cys339Tyr	missense	Exon 6 of 6	ENSP00000422464.1	Q9NRA1-1
	PDGFC	ENST00000274071.6	TSL:1	n.*924G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000274071.2	J3KN71
	PDGFC	ENST00000274071.6	TSL:1	n.*924G>A		3_prime_UTR	Exon 7 of 7	ENSP00000274071.2	J3KN71

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450460 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722354

⚠️ 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: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101692

Other (OTH) AF: 0.00 AC: 0 AN: 59968

⚠️ 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 Cov.: 31

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.45		Gain of phosphorylation at C339 (P = 0.0297)
MVP		0.63
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.85
gMVP		1.0
Mutation Taster		=6/94	disease causing

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

hg19: chr4-157684264; COSMIC: COSV56851231; COSMIC: COSV56851231;