4-8270311-G-T

Variant names:

• chr4-8270311-G-T
• rs956501315
• NM_053044.5:c.343G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_053044.5(HTRA3):​c.343G>T​(p.Gly115Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G115R) has been classified 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.52
• Publications: 0 publications found

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]

ENSG00000298837 (HGNC:58728):

LOC105374373 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053044.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA3	NM_053044.5	MANE Select	c.343G>T	p.Gly115Trp	missense	Exon 1 of 9	NP_444272.1	P83110-1
	HTRA3	NM_001297559.3		c.343G>T	p.Gly115Trp	missense	Exon 1 of 7	NP_001284488.1	P83110-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA3	ENST00000307358.7	TSL:1 MANE Select	c.343G>T	p.Gly115Trp	missense	Exon 1 of 9	ENSP00000303766.2	P83110-1
	HTRA3	ENST00000382512.3	TSL:1	c.343G>T	p.Gly115Trp	missense	Exon 1 of 7	ENSP00000371952.3	P83110-2
	HTRA3	ENST00000968934.1		c.343G>T	p.Gly115Trp	missense	Exon 1 of 9	ENSP00000638993.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1314570 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 644774

African (AFR) AF: 0.00 AC: 0 AN: 26230

American (AMR) AF: 0.00 AC: 0 AN: 25178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22526

East Asian (EAS) AF: 0.00 AC: 0 AN: 30018

South Asian (SAS) AF: 0.00 AC: 0 AN: 71554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3864

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048276

Other (OTH) AF: 0.00 AC: 0 AN: 54564

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.62
MVP		0.37
MPC		2.2
ClinPred		0.90	D
GERP RS		2.7
Varity_R		0.19
gMVP		0.46
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs956501315; hg19: chr4-8272038;