Genetic Variant HTRA3:p.Ala27Ser (chr4-8270047-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_053044.5(HTRA3):c.79G>T(p.Ala27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HTRA3
NM_053044.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.763

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0332824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA3	NM_053044.5 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 9	ENST00000307358.7	NP_444272.1	P83110-1
HTRA3	NM_001297559.3 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 7		NP_001284488.1	P83110-2
HTRA3	XM_011513596.4 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 7		XP_011511898.1
LOC105374373	XR_001741572.2 link	n.75+60C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA3	ENST00000307358.7 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 9	1	NM_053044.5	ENSP00000303766.2		P83110-1
HTRA3	ENST00000382512.3 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 7	1		ENSP00000371952.3		P83110-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1289626

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

636408

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79G>T (p.A27S) alteration is located in exon 1 (coding exon 1) of the HTRA3 gene. This alteration results from a G to T substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 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

0.073

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.11

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.020

Sift

Benign

0.52

T;T

Sift4G

Benign

0.75

T;T

Polyphen

0.043

B;B

Vest4

0.075

MutPred

0.086

Gain of glycosylation at A27 (P = 0.006);Gain of glycosylation at A27 (P = 0.006);

MVP

0.16

MPC

0.85

ClinPred

0.090

GERP RS

-0.29

Varity_R

0.13

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over