12-6839304-T-C

Variant names:

• chr12-6839304-T-C
• rs1129649
• NM_014262.5:c.2054T>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.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. 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 0.36 (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
• Publications: 45 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=0.0015980005).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 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.2054T>C	p.Ile685Thr	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.2054T>C	p.Ile685Thr	missense	Exon 15 of 15	ENSP00000478600.1	Q8IVL6-1
	P3H3	ENST00000612048.4	TSL:1	n.1587T>C		non_coding_transcript_exon	Exon 14 of 14
	P3H3	ENST00000913254.1		c.2084T>C	p.Ile695Thr	missense	Exon 15 of 15	ENSP00000583313.1

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

GnomAD2 exomes AF: 0.359 AC: 57177 AN: 159106 AF XY: 0.361

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 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

African (AFR) AF: 0.384 AC: 12162 AN: 31668

American (AMR) AF: 0.345 AC: 12346 AN: 35766

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9297 AN: 25192

East Asian (EAS) AF: 0.372 AC: 13345 AN: 35852

South Asian (SAS) AF: 0.381 AC: 30275 AN: 79434

European-Finnish (FIN) AF: 0.329 AC: 16227 AN: 49330

Middle Eastern (MID) AF: 0.357 AC: 2031 AN: 5696

European-Non Finnish (NFE) AF: 0.364 AC: 393053 AN: 1079854

Other (OTH) AF: 0.374 AC: 21726 AN: 58162

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

African (AFR) AF: 0.384 AC: 15840 AN: 41240

American (AMR) AF: 0.374 AC: 5690 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1295 AN: 3468

East Asian (EAS) AF: 0.392 AC: 2007 AN: 5126

South Asian (SAS) AF: 0.369 AC: 1769 AN: 4796

European-Finnish (FIN) AF: 0.337 AC: 3535 AN: 10498

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 23986 AN: 67818

Other (OTH) AF: 0.369 AC: 776 AN: 2104

Alfa AF: 0.354 Hom.: 40427

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 v4.9

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
PhyloP100		0.70
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
Mutation Taster		=91/9	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: rs1129649; hg19: chr12-6948468;