chr3-48990426-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

P4HTM Gene-Disease associations (from GenCC):

• hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000235236 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177939.3. 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
	P4HTM	NM_177939.3	MANE Select	c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	NP_808808.1	Q9NXG6-1
	P4HTM	NM_177938.2		c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	NP_808807.2	Q9NXG6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HTM	ENST00000383729.9	TSL:1 MANE Select	c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	ENSP00000373235.4	Q9NXG6-1
	P4HTM	ENST00000343546.8	TSL:1	c.170C>T	p.Ser57Leu	missense	Exon 1 of 9	ENSP00000341422.4	Q9NXG6-3
	P4HTM	ENST00000475629.5	TSL:1	c.89C>T	p.Ser30Leu	missense	Exon 1 of 3	ENSP00000477191.1	A0A0C4DGS7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.0079	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.17
MutPred		0.42		Gain of sheet (P = 0.0477)
MVP		0.68
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.025	Neutral
Varity_R		0.68
gMVP		0.76
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

hg19: chr3-49027859;