chr10-73045005-G-T

Variant names:

• chr10-73045005-G-T
• rs145054165
• NM_001017962.3:c.1124C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017962.3(P4HA1):​c.1124C>A​(p.Thr375Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T375M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: P4HA1 NM_001017962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.57
• Publications: 1 publications found

Genes affected

P4HA1 (HGNC:8546): (prolyl 4-hydroxylase subunit alpha 1) 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. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA1	NM_001017962.3	c.1124C>A	p.Thr375Lys	missense_variant	Exon 9 of 15	ENST00000394890.7	NP_001017962.1
P4HA1	NM_001142595.2	c.1124C>A	p.Thr375Lys	missense_variant	Exon 10 of 16		NP_001136067.1
P4HA1	NM_000917.4	c.1078-1048C>A		intron_variant	Intron 8 of 14		NP_000908.2
P4HA1	NM_001142596.2	c.1078-1048C>A		intron_variant	Intron 8 of 13		NP_001136068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA1	ENST00000394890.7	c.1124C>A	p.Thr375Lys	missense_variant	Exon 9 of 15	1	NM_001017962.3	ENSP00000378353.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249216 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461092 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726914

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000448 AC: 2 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111490

Other (OTH) AF: 0.00 AC: 0 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		9.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.63	P;P
Vest4		0.82
MutPred		0.48		Gain of ubiquitination at T375 (P = 0.017);Gain of ubiquitination at T375 (P = 0.017);
MVP		0.85
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.25
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145054165; hg19: chr10-74804763;