4-8270072-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_053044.5(HTRA3):​c.104C>G​(p.Pro35Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,516,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

HTRA3
NM_053044.5 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.17
Variant links:
Genes affected
HTRA3 (HGNC:30406): (HtrA serine peptidase 3) Enables endopeptidase activity; identical protein binding activity; and serine-type peptidase activity. Involved in proteolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3093032).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HTRA3NM_053044.5 linkc.104C>G p.Pro35Arg missense_variant Exon 1 of 9 ENST00000307358.7 NP_444272.1 P83110-1
HTRA3NM_001297559.3 linkc.104C>G p.Pro35Arg missense_variant Exon 1 of 7 NP_001284488.1 P83110-2
HTRA3XM_011513596.4 linkc.104C>G p.Pro35Arg missense_variant Exon 1 of 7 XP_011511898.1
LOC105374373XR_001741572.2 linkn.75+35G>C intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HTRA3ENST00000307358.7 linkc.104C>G p.Pro35Arg missense_variant Exon 1 of 9 1 NM_053044.5 ENSP00000303766.2 P83110-1
HTRA3ENST00000382512.3 linkc.104C>G p.Pro35Arg missense_variant Exon 1 of 7 1 ENSP00000371952.3 P83110-2

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
151898
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000214
AC:
3
AN:
140322
Hom.:
0
AF XY:
0.0000370
AC XY:
3
AN XY:
80978
show subpopulations
Gnomad AFR exome
AF:
0.000545
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.00000733
AC:
10
AN:
1364080
Hom.:
0
Cov.:
31
AF XY:
0.00000443
AC XY:
3
AN XY:
677160
show subpopulations
Gnomad4 AFR exome
AF:
0.000356
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152006
Hom.:
0
Cov.:
33
AF XY:
0.000135
AC XY:
10
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.0000274
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.104C>G (p.P35R) alteration is located in exon 1 (coding exon 1) of the HTRA3 gene. This alteration results from a C to G substitution at nucleotide position 104, causing the proline (P) at amino acid position 35 to be replaced by an arginine (R). 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
0.16
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Benign
0.26
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.035
D;D
Polyphen
1.0
D;D
Vest4
0.55
MutPred
0.29
Loss of glycosylation at S36 (P = 0.0649);Loss of glycosylation at S36 (P = 0.0649);
MVP
0.81
MPC
2.0
ClinPred
0.90
D
GERP RS
2.4
Varity_R
0.59
gMVP
0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs528115462; hg19: chr4-8271799; API