Genetic Variant HTRA3:p.Leu121Met (chr4-8270329-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_053044.5(HTRA3):c.361C>A(p.Leu121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,439,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

HTRA3
NM_053044.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11196974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA3	NM_053044.5 link	c.361C>A	p.Leu121Met	missense_variant	Exon 1 of 9	ENST00000307358.7	NP_444272.1	P83110-1
HTRA3	NM_001297559.3 link	c.361C>A	p.Leu121Met	missense_variant	Exon 1 of 7		NP_001284488.1	P83110-2
HTRA3	XM_011513596.4 link	c.361C>A	p.Leu121Met	missense_variant	Exon 1 of 7		XP_011511898.1
LOC105374373	XR_001741572.2 link	n.-148G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA3	ENST00000307358.7 link	c.361C>A	p.Leu121Met	missense_variant	Exon 1 of 9	1	NM_053044.5	ENSP00000303766.2		P83110-1
HTRA3	ENST00000382512.3 link	c.361C>A	p.Leu121Met	missense_variant	Exon 1 of 7	1		ENSP00000371952.3		P83110-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000210

AC:

AN:

47718

Hom.:

AF XY:

0.00

AC XY:

AN XY:

28168

show subpopulations

Gnomad AFR exome

AF:

0.00111

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:

0.00000233

AC:

AN:

1287042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

629190

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.0000197

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

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:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361C>A (p.L121M) alteration is located in exon 1 (coding exon 1) of the HTRA3 gene. This alteration results from a C to A substitution at nucleotide position 361, causing the leucine (L) at amino acid position 121 to be replaced by a methionine (M). 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

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.87

D;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.049

Sift

Benign

0.10

T;T

Sift4G

Benign

0.086

T;T

Polyphen

0.75

P;P

Vest4

0.31

MVP

0.23

MPC

1.8

ClinPred

0.25

GERP RS

2.6

Varity_R

0.17

gMVP

0.34

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