chr3-48990426-C-T

Variant names:

• chr3-48990426-C-T
• NM_177939.3:c.170C>T

Variant summary

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

The NM_177939.3(P4HTM):​c.170C>T​(p.Ser57Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HTM NM_177939.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

Genes affected

P4HTM (HGNC:28858): (prolyl 4-hydroxylase, transmembrane) The product of this gene belongs to the family of prolyl 4-hydroxylases. This protein is a prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia. It plays a role in adaptation to hypoxia and may be related to cellular oxygen sensing. Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
P4HTM	NM_177939.3	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 9	ENST00000383729.9	NP_808808.1
P4HTM	NM_177938.2	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 9		NP_808807.2
P4HTM	XM_047448367.1	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 5		XP_047304323.1
P4HTM	XR_007095696.1	n.186C>T		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HTM	ENST00000383729.9	c.170C>T	p.Ser57Leu	missense_variant	Exon 1 of 9	1	NM_177939.3	ENSP00000373235.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.170C>T (p.S57L) alteration is located in exon 1 (coding exon 1) of the P4HTM gene. This alteration results from a C to T substitution at nucleotide position 170, causing the serine (S) at amino acid position 57 to be replaced by a leucine (L). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.0079	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N;N;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.018	D;D;T
Polyphen		0.99	D;D;.
Vest4		0.17
MutPred		0.42		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.68
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-49027859;