10-73014217-G-A

Variant names:

• chr10-73014217-G-A
• rs73272315
• NM_001017962.3:c.1368+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017962.3(P4HA1):​c.1368+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,593,318 control chromosomes in the GnomAD database, including 331 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (164 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (167 hom.)
• Consequence: P4HA1 NM_001017962.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001145
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380
• Publications: 2 publications found

Genes affected

P4HA1 (HGNC:8546): (prolyl 4-hydroxylase subunit alpha 1) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-73014217-G-A is Benign according to our data. Variant chr10-73014217-G-A is described in ClinVar as [Benign]. Clinvar id is 784085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA1	NM_001017962.3	c.1368+7C>T		splice_region_variant, intron_variant	Intron 12 of 14	ENST00000394890.7	NP_001017962.1
P4HA1	NM_000917.4	c.1368+7C>T		splice_region_variant, intron_variant	Intron 12 of 14		NP_000908.2
P4HA1	NM_001142595.2	c.1368+7C>T		splice_region_variant, intron_variant	Intron 13 of 15		NP_001136067.1
P4HA1	NM_001142596.2	c.1314+7C>T		splice_region_variant, intron_variant	Intron 11 of 13		NP_001136068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA1	ENST00000394890.7	c.1368+7C>T		splice_region_variant, intron_variant	Intron 12 of 14	1	NM_001017962.3	ENSP00000378353.2

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3904 AN: 152008 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00748 AC: 1868 AN: 249594 AF XY: 0.00577

Gnomad AFR exome AF: 0.0906

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00296 AC: 4270 AN: 1441192 Hom.: 167 Cov.: 27 AF XY: 0.00259 AC XY: 1860 AN XY: 718182

African (AFR) AF: 0.0905 AC: 2978 AN: 32924

American (AMR) AF: 0.00418 AC: 186 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 311 AN: 25986

East Asian (EAS) AF: 0.00172 AC: 68 AN: 39558

South Asian (SAS) AF: 0.000211 AC: 18 AN: 85442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00454 AC: 26 AN: 5724

European-Non Finnish (NFE) AF: 0.000288 AC: 315 AN: 1094086

Other (OTH) AF: 0.00617 AC: 368 AN: 59672

GnomAD4 genome AF: 0.0257 AC: 3905 AN: 152126 Hom.: 164 Cov.: 32 AF XY: 0.0248 AC XY: 1841 AN XY: 74376

African (AFR) AF: 0.0872 AC: 3618 AN: 41470

American (AMR) AF: 0.00922 AC: 141 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67996

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0155 Hom.: 57

Bravo AF: 0.0290

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000654

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.67
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs73272315; hg19: chr10-74773975;