10-122506796-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_002775.5(HTRA1):​c.883G>C​(p.Gly295Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

HTRA1
NM_002775.5 missense

Scores

17
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.80
Variant links:
Genes affected
HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002775.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HTRA1NM_002775.5 linkc.883G>C p.Gly295Arg missense_variant Exon 4 of 9 ENST00000368984.8 NP_002766.1 Q92743

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HTRA1ENST00000368984.8 linkc.883G>C p.Gly295Arg missense_variant Exon 4 of 9 1 NM_002775.5 ENSP00000357980.3 Q92743
HTRA1ENST00000648167.1 linkc.565G>C p.Gly189Arg missense_variant Exon 4 of 9 ENSP00000498033.1 A0A3B3IU24
HTRA1ENST00000420892.1 linkc.106G>C p.Gly36Arg missense_variant Exon 1 of 6 2 ENSP00000412676.1 H0Y7G9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251248
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135846
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461682
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
.;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
.;H;.
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-7.8
.;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
.;D;D
Sift4G
Pathogenic
0.0010
.;D;D
Polyphen
1.0
.;D;.
Vest4
0.98
MutPred
0.89
.;Loss of sheet (P = 0.0181);.;
MVP
0.98
MPC
1.6
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.97
gMVP
0.97

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs587776873; hg19: chr10-124266312; API