12-6839364-T-C

Variant names:

• chr12-6839364-T-C
• rs3213431
• NM_014262.5:c.2114T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014262.5(P3H3):​c.2114T>C​(p.Met705Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,553,340 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0042 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (304 hom.)
• Consequence: P3H3 NM_014262.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.630
• Publications: 9 publications found

Genes affected

P3H3 (HGNC:19318): (prolyl 3-hydroxylase 3) The protein encoded by this gene belongs to the leprecan family of proteoglycans, which function as collagen prolyl hydroxylases that are required for proper collagen biosynthesis, folding and assembly. This protein, like other family members, is thought to reside in the endoplasmic reticulum. Epigenetic inactivation of this gene is associated with breast and other cancers, suggesting that it may function as a tumor suppressor. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015749931).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014262.5. 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
	P3H3	NM_014262.5	MANE Select	c.2114T>C	p.Met705Thr	missense	Exon 15 of 15	NP_055077.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H3	ENST00000290510.10	TSL:1 MANE Select	c.2114T>C	p.Met705Thr	missense	Exon 15 of 15	ENSP00000478600.1	Q8IVL6-1
	P3H3	ENST00000612048.4	TSL:1	n.1647T>C		non_coding_transcript_exon	Exon 14 of 14
	P3H3	ENST00000913254.1		c.2144T>C	p.Met715Thr	missense	Exon 15 of 15	ENSP00000583313.1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 631 AN: 151808 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00911 AC: 1459 AN: 160148 AF XY: 0.00909

Gnomad AFR exome AF: 0.000948

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000949

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00396 AC: 5554 AN: 1401414 Hom.: 304 Cov.: 35 AF XY: 0.00394 AC XY: 2725 AN XY: 691366

African (AFR) AF: 0.000347 AC: 11 AN: 31668

American (AMR) AF: 0.000223 AC: 8 AN: 35872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25262

East Asian (EAS) AF: 0.128 AC: 4576 AN: 35828

South Asian (SAS) AF: 0.00601 AC: 477 AN: 79362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49466

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.0000463 AC: 50 AN: 1080052

Other (OTH) AF: 0.00737 AC: 429 AN: 58204

GnomAD4 genome AF: 0.00417 AC: 633 AN: 151926 Hom.: 29 Cov.: 32 AF XY: 0.00482 AC XY: 358 AN XY: 74248

African (AFR) AF: 0.000531 AC: 22 AN: 41418

American (AMR) AF: 0.00196 AC: 30 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.102 AC: 525 AN: 5168

South Asian (SAS) AF: 0.00852 AC: 41 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67908

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.000841 Hom.: 1

Bravo AF: 0.00494

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000728 AC: 3

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00450 AC: 468

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.5
DANN	Benign	0.71
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.63
REVEL	Benign	0.061
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.095
MVP		0.014
ClinPred		0.0012	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.19
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3213431; hg19: chr12-6948528;