10-73051172-A-T

Position:

• chr10-73051172-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017962.3(P4HA1):​c.781T>A​(p.Ser261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HA1 NM_001017962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1066381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P4HA1	NM_001017962.3	c.781T>A	p.Ser261Thr	missense_variant	7/15	ENST00000394890.7
P4HA1	NM_000917.4	c.781T>A	p.Ser261Thr	missense_variant	7/15
P4HA1	NM_001142595.2	c.781T>A	p.Ser261Thr	missense_variant	8/16
P4HA1	NM_001142596.2	c.781T>A	p.Ser261Thr	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P4HA1	ENST00000394890.7	c.781T>A	p.Ser261Thr	missense_variant	7/15	1	NM_001017962.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.781T>A (p.S261T) alteration is located in exon 8 (coding exon 6) of the P4HA1 gene. This alteration results from a T to A substitution at nucleotide position 781, causing the serine (S) at amino acid position 261 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.22	T;.;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	.;.;T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.64	T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T
Polyphen		0.010	B;.;B;.;.
Vest4		0.13
MutPred		0.17		Loss of helix (P = 0.0821);Loss of helix (P = 0.0821);Loss of helix (P = 0.0821);Loss of helix (P = 0.0821);Loss of helix (P = 0.0821);
MVP		0.79
ClinPred		0.29	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.35

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-74810930;