rs61100157

Variant names:

• chr1-42757837-G-A
• rs61100157
• NM_022356.4:c.1026C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_022356.4(P3H1):​c.1026C>T​(p.Ala342Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,186 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 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 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.214
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-42757837-G-A is Benign according to our data. Variant chr1-42757837-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379768.
• BP7: Synonymous conserved (PhyloP=0.214 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H1	NM_022356.4	MANE Select	c.1026C>T	p.Ala342Ala	synonymous	Exon 5 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1026C>T	p.Ala342Ala	synonymous	Exon 5 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1026C>T	p.Ala342Ala	synonymous	Exon 5 of 15	NP_001139761.1	Q32P28-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H1	ENST00000296388.10	TSL:1 MANE Select	c.1026C>T	p.Ala342Ala	synonymous	Exon 5 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1026C>T	p.Ala342Ala	synonymous	Exon 5 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.1350C>T	p.Ala450Ala	synonymous	Exon 5 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2224 AN: 152186 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

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: 0.000206

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00396 AC: 995 AN: 251492 AF XY: 0.00304

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: 2257 AN: 1461882 Hom.: 52 Cov.: 32 AF XY: 0.00131 AC XY: 956 AN XY: 727238

African (AFR) AF: 0.0531 AC: 1779 AN: 33478

American (AMR) AF: 0.00349 AC: 156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1112002

Other (OTH) AF: 0.00346 AC: 209 AN: 60396

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152304 Hom.: 62 Cov.: 32 AF XY: 0.0144 AC XY: 1074 AN XY: 74482

African (AFR) AF: 0.0504 AC: 2095 AN: 41558

American (AMR) AF: 0.00640 AC: 98 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68026

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00647 Hom.: 12

Bravo AF: 0.0166

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Osteogenesis imperfecta type 8 (3)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.21
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61100157; hg19: chr1-43223508;