17-41802962-C-G

Variant names:

• chr17-41802962-C-G
• rs532282174
• NM_006455.3:c.1309G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006455.3(P3H4):​c.1309G>C​(p.Ala437Pro) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P3H4 NM_006455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214
• Publications: 0 publications found

Genes affected

P3H4 (HGNC:16946): (prolyl 3-hydroxylase family member 4 (inactive)) This nucleolar protein was first characterized because it was an autoantigen in cases on interstitial cystitis. The protein, with a predicted molecular weight of 50 kDa, appears to be localized in the particulate compartment of the interphase nucleolus, with a distribution distinct from that of nucleolar protein B23. During mitosis it is associated with chromosomes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03800389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H4	NM_006455.3	c.1309G>C	p.Ala437Pro	missense_variant	Exon 8 of 8	ENST00000393928.6	NP_006446.1
P3H4	XM_047435137.1	c.1492G>C	p.Ala498Pro	missense_variant	Exon 8 of 8		XP_047291093.1
P3H4	XM_047435138.1	c.1347G>C	p.Ser449Ser	synonymous_variant	Exon 7 of 7		XP_047291094.1
P3H4	XM_006721640.5	c.1164G>C	p.Ser388Ser	synonymous_variant	Exon 7 of 7		XP_006721703.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H4	ENST00000393928.6	c.1309G>C	p.Ala437Pro	missense_variant	Exon 8 of 8	1	NM_006455.3	ENSP00000377505.1
P3H4	ENST00000355468.7	c.1309G>C	p.Ala437Pro	missense_variant	Exon 9 of 9	2		ENSP00000347649.2
P3H4	ENST00000465097.1	n.214G>C		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000435615.1
P3H4	ENST00000484247.1	n.858G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1309G>C (p.A437P) alteration is located in exon 8 (coding exon 8) of the P3H4 gene. This alteration results from a G to C substitution at nucleotide position 1309, causing the alanine (A) at amino acid position 437 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;N
PhyloP100		0.21
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.066	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.23		Gain of glycosylation at A437 (P = 0.0218);Gain of glycosylation at A437 (P = 0.0218);
MVP		0.014
MPC		0.33
ClinPred		0.25	T
GERP RS		-0.41
Varity_R		0.052
gMVP		0.22

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: rs532282174; hg19: chr17-39959214;