rs1129649

chr12-6839304-T-Cchr12-6839304-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014262.5(P3H3):c.2054T>C(p.Ile685Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,552,430 control chromosomes in the GnomAD database, including 104,063 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.36 (10210 hom., cov: 31)
  • Exomes 𝑓: 0.36 (93853 hom.)
• Consequence: P3H3 NM_014262.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.698

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015980005).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H3	NM_014262.5	c.2054T>C	p.Ile685Thr	missense_variant	15/15	ENST00000290510.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H3	ENST00000290510.10	c.2054T>C	p.Ile685Thr	missense_variant	15/15	1	NM_014262.5	P1
P3H3	ENST00000612048.4	n.1587T>C		non_coding_transcript_exon_variant	14/14	1
P3H3	ENST00000536140.5	n.2684T>C		non_coding_transcript_exon_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55160 AN: 151358 Hom.: 10205 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.359 AC: 57177 AN: 159106 Hom.: 10423 AF XY: 0.361 AC XY: 30362 AN XY: 83996

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.397

Gnomad SAS exome AF: 0.379

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.364 AC: 510462 AN: 1400954 Hom.: 93853 Cov.: 49 AF XY: 0.365 AC XY: 252099 AN XY: 691178

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.372

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.364 AC: 55185 AN: 151476 Hom.: 10210 Cov.: 31 AF XY: 0.363 AC XY: 26849 AN XY: 73982

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.392

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.369

Alfa AF: 0.349 Hom.: 19585

Bravo AF: 0.367

TwinsUK AF: 0.365 AC: 1353

ALSPAC AF: 0.371 AC: 1430

ESP6500AA AF: 0.358 AC: 1469

ESP6500EA AF: 0.340 AC: 2851

ExAC AF: 0.268 AC: 26023

Asia WGS AF: 0.371 AC: 1286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	14
Dann	Benign	0.81
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P
REVEL	Benign	0.076
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.014
ClinPred		0.00092	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.029
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1129649; hg19: chr12-6948468;