4-8270311-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_053044.5(HTRA3):​c.343G>C​(p.Gly115Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000304 in 1,314,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27146083).

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>C	p.Gly115Arg	missense	Exon 1 of 9	NP_444272.1	P83110-1
	HTRA3	NM_001297559.3		c.343G>C	p.Gly115Arg	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>C	p.Gly115Arg	missense	Exon 1 of 9	ENSP00000303766.2	P83110-1
	HTRA3	ENST00000382512.3	TSL:1	c.343G>C	p.Gly115Arg	missense	Exon 1 of 7	ENSP00000371952.3	P83110-2
	HTRA3	ENST00000968934.1		c.343G>C	p.Gly115Arg	missense	Exon 1 of 9	ENSP00000638993.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000140 AC: 1 AN: 71436 AF XY: 0.0000244

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1314570 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 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: 0.00000382 AC: 4 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	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.57	N
PhyloP100		5.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.068
Sift	Benign	0.52	T
Sift4G	Benign	0.69	T
Polyphen		0.0020	B
Vest4		0.69
MutPred		0.59		Gain of MoRF binding (P = 0.0111)
MVP		0.17
MPC		1.1
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.10
gMVP		0.46
Mutation Taster		=72/28	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;