chr11-74268196-C-G

Variant names:

• chr11-74268196-C-G
• rs147167718
• NM_182904.5:c.1513G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_182904.5(P4HA3):​c.1513G>C​(p.Asp505His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,614,108 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (5 hom.)
• Consequence: P4HA3 NM_182904.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47
• Publications: 3 publications found

Genes affected

P4HA3 (HGNC:30135): (prolyl 4-hydroxylase subunit alpha 3) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044900894).
• BP6: Variant 11-74268196-C-G is Benign according to our data. Variant chr11-74268196-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2642147.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182904.5. 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
	P4HA3	NM_182904.5	MANE Select	c.1513G>C	p.Asp505His	missense	Exon 12 of 13	NP_878907.1	Q7Z4N8-1
	P4HA3	NM_001288748.2		c.1506G>C	p.Gly502Gly	synonymous	Exon 12 of 13	NP_001275677.1	Q7Z4N8-3
	P4HA3	NR_110031.2		n.1348G>C		non_coding_transcript_exon	Exon 11 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HA3	ENST00000331597.9	TSL:1 MANE Select	c.1513G>C	p.Asp505His	missense	Exon 12 of 13	ENSP00000332170.4	Q7Z4N8-1
	P4HA3	ENST00000524388.5	TSL:1	n.*915G>C		non_coding_transcript_exon	Exon 13 of 16	ENSP00000433860.1	Q7Z4N8-2
	P4HA3	ENST00000525968.1	TSL:1	n.*1004G>C		non_coding_transcript_exon	Exon 11 of 12	ENSP00000431227.1	E9PM97

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000928 AC: 233 AN: 251184 AF XY: 0.00112

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000915 AC: 1338 AN: 1461786 Hom.: 5 Cov.: 30 AF XY: 0.000985 AC XY: 716 AN XY: 727186

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86238

European-Finnish (FIN) AF: 0.00221 AC: 118 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000926 AC: 1030 AN: 1111954

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000988 AC: 120

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.48	T
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.67
MPC		0.40
ClinPred		0.12	T
GERP RS		3.9
Varity_R		0.74
Mutation Taster		=51/49	polymorphism

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: rs147167718; hg19: chr11-73979241; COSMIC: COSV105825154;