17-41807980-C-T

Variant names:

• chr17-41807980-C-T
• rs138564388
• NM_006455.3:c.941G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006455.3(P3H4):​c.941G>A​(p.Arg314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: P3H4 NM_006455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10419962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H4	NM_006455.3	c.941G>A	p.Arg314His	missense_variant	Exon 5 of 8	ENST00000393928.6	NP_006446.1
P3H4	XM_047435137.1	c.1124G>A	p.Arg375His	missense_variant	Exon 5 of 8		XP_047291093.1
P3H4	XM_047435138.1	c.1124G>A	p.Arg375His	missense_variant	Exon 5 of 7		XP_047291094.1
P3H4	XM_006721640.5	c.941G>A	p.Arg314His	missense_variant	Exon 5 of 7		XP_006721703.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H4	ENST00000393928.6	c.941G>A	p.Arg314His	missense_variant	Exon 5 of 8	1	NM_006455.3	ENSP00000377505.1
P3H4	ENST00000355468.7	c.941G>A	p.Arg314His	missense_variant	Exon 6 of 9	2		ENSP00000347649.2
P3H4	ENST00000592026.1	c.455G>A	p.Arg152His	missense_variant	Exon 4 of 5	5		ENSP00000468174.1
P3H4	ENST00000587455.1	n.482-1101G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000247 AC: 62 AN: 250736 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000468

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461614 Hom.: 0 Cov.: 30 AF XY: 0.000183 AC XY: 133 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1111882

Other (OTH) AF: 0.0000497 AC: 3 AN: 60384

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.941G>A (p.R314H) alteration is located in exon 5 (coding exon 5) of the P3H4 gene. This alteration results from a G to A substitution at nucleotide position 941, causing the arginine (R) at amino acid position 314 to be replaced by a histidine (H). 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	0.099
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.034
Sift	Benign	0.10	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.025	B;B
Vest4		0.38
MVP		0.048
MPC		0.93
ClinPred		0.30	T
GERP RS		3.2
Varity_R		0.091
gMVP		0.23
Mutation Taster		=83/17	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

dbSNP: rs138564388; hg19: chr17-39964232; COSMIC: COSV58635212; COSMIC: COSV58635212;