dbSNP rs76871760: P3H1:c.1569+3A>G (chr1-42752271-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_022356.4(P3H1):c.1569+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,611,898 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.015 ( 62 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 52 hom. )

Consequence

P3H1
NM_022356.4 splice_region, intron

Scores

Splicing: ADA: 0.08602

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.13

Publications

0 publications found

Variant links:

Genes affected

P3H1 (HGNC:19316): (prolyl 3-hydroxylase 1) This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]

P3H1 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
osteogenesis imperfecta type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

P3H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 1-42752271-T-C is Benign according to our data. Variant chr1-42752271-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379770.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
P3H1	NM_022356.4	MANE Select	c.1569+3A>G	splice_region intron	N/A	NP_071751.3
P3H1	NM_001243246.2		c.1569+3A>G	splice_region intron	N/A	NP_001230175.1	Q32P28-3
P3H1	NM_001146289.2		c.1569+3A>G	splice_region intron	N/A	NP_001139761.1	Q32P28-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
P3H1	ENST00000296388.10	TSL:1 MANE Select	c.1569+3A>G	splice_region intron	N/A	ENSP00000296388.5	Q32P28-1
P3H1	ENST00000397054.7	TSL:1	c.1569+3A>G	splice_region intron	N/A	ENSP00000380245.3	Q32P28-4
P3H1	ENST00000907902.1		c.1893+3A>G	splice_region intron	N/A	ENSP00000577961.1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2220

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0505

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00815

GnomAD2 exomes

AF:

0.00396

AC:

995

AN:

251432

AF XY:

0.00304

show subpopulations

Gnomad AFR exome

AF:

0.0520

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00154

AC:

2246

AN:

1459782

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

953

AN XY:

726354

show subpopulations

African (AFR)

AF:

0.0530

AC:

1769

AN:

33404

American (AMR)

AF:

0.00349

AC:

156

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000856

AC:

AN:

1110162

Other (OTH)

AF:

0.00346

AC:

209

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2224

AN:

152116

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0505

AC:

2092

AN:

41466

American (AMR)

AF:

0.00634

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67966

Other (OTH)

AF:

0.00806

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00823

Hom.:

Bravo

AF:

0.0166

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Osteogenesis imperfecta type 8 (3)

not specified (2)

Osteogenesis imperfecta (1)

Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.1

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.086

dbscSNV1_RF

Benign

0.27

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over