Genetic Variant HTRA3:p.Gly63Ser (chr4-8270155-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_053044.5(HTRA3):c.187G>A(p.Gly63Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000719 in 1,390,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

HTRA3
NM_053044.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.06

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]

HTRA3 links:

LOC105374373 (HGNC:):

LOC105374373 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA3	NM_053044.5 link	c.187G>A	p.Gly63Ser	missense_variant	Exon 1 of 9	ENST00000307358.7	NP_444272.1	P83110-1
HTRA3	NM_001297559.3 link	c.187G>A	p.Gly63Ser	missense_variant	Exon 1 of 7		NP_001284488.1	P83110-2
HTRA3	XM_011513596.4 link	c.187G>A	p.Gly63Ser	missense_variant	Exon 1 of 7		XP_011511898.1
LOC105374373	XR_001741572.2 link	n.27C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA3	ENST00000307358.7 link	c.187G>A	p.Gly63Ser	missense_variant	Exon 1 of 9	1	NM_053044.5	ENSP00000303766.2		P83110-1
HTRA3	ENST00000382512.3 link	c.187G>A	p.Gly63Ser	missense_variant	Exon 1 of 7	1		ENSP00000371952.3		P83110-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

156418

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

90014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000205

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:

0.00000719

AC:

AN:

1390514

Hom.:

Cov.:

AF XY:

0.00000868

AC XY:

AN XY:

691094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000274

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

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187G>A (p.G63S) alteration is located in exon 1 (coding exon 1) of the HTRA3 gene. This alteration results from a G to A substitution at nucleotide position 187, causing the glycine (G) at amino acid position 63 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.32

MutPred

0.39

Gain of glycosylation at G63 (P = 0.0019);Gain of glycosylation at G63 (P = 0.0019);

MVP

0.82

MPC

2.0

ClinPred

0.90

GERP RS

3.3

Varity_R

0.87

gMVP

0.75

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over