10-73030353-T-G

Variant names:

• chr10-73030353-T-G
• rs201077792
• NM_001017962.3:c.1166A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017962.3(P4HA1):​c.1166A>C​(p.Tyr389Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y389C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HA1 NM_001017962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA1	NM_001017962.3	c.1166A>C	p.Tyr389Ser	missense_variant	Exon 10 of 15	ENST00000394890.7	NP_001017962.1
P4HA1	NM_000917.4	c.1166A>C	p.Tyr389Ser	missense_variant	Exon 10 of 15		NP_000908.2
P4HA1	NM_001142595.2	c.1166A>C	p.Tyr389Ser	missense_variant	Exon 11 of 16		NP_001136067.1
P4HA1	NM_001142596.2	c.1166A>C	p.Tyr389Ser	missense_variant	Exon 10 of 14		NP_001136068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA1	ENST00000394890.7	c.1166A>C	p.Tyr389Ser	missense_variant	Exon 10 of 15	1	NM_001017962.3	ENSP00000378353.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.33	T;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	.;.;D;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L;L
PhyloP100		5.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.84	T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.0090	B;.;B;.;.
Vest4		0.66
MutPred		0.39		Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
MVP		0.82
ClinPred		0.87	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.81
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201077792; hg19: chr10-74790111;