3-48990488-C-G

Variant names:

• chr3-48990488-C-G
• NM_177939.3:c.232C>G

Variant summary

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

The NM_177939.3(P4HTM):​c.232C>G​(p.Leu78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: P4HTM NM_177939.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.724

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.232C>G	p.Leu78Val	missense_variant	Exon 1 of 9	ENST00000383729.9	NP_808808.1
P4HTM	NM_177938.2	c.232C>G	p.Leu78Val	missense_variant	Exon 1 of 9		NP_808807.2
P4HTM	XM_047448367.1	c.232C>G	p.Leu78Val	missense_variant	Exon 1 of 5		XP_047304323.1
P4HTM	XR_007095696.1	n.248C>G		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.232C>G	p.Leu78Val	missense_variant	Exon 1 of 9	1	NM_177939.3	ENSP00000373235.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459224 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

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

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232C>G (p.L78V) alteration is located in exon 1 (coding exon 1) of the P4HTM gene. This alteration results from a C to G substitution at nucleotide position 232, causing the leucine (L) at amino acid position 78 to be replaced by a valine (V). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.088	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.87	N;N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.025	D;D;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.22
MutPred		0.25		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);.;
MVP		0.77
MPC		2.1
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.77

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: chr3-49027921;