4-8269996-G-C

Variant names:

• chr4-8269996-G-C
• NM_053044.5:c.28G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053044.5(HTRA3):​c.28G>C​(p.Ala10Pro) 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)
• Consequence: HTRA3 NM_053044.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.374

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]

LOC105374373 (HGNC:):

ACMG classification

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=0.17452767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA3	NM_053044.5	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 9	ENST00000307358.7	NP_444272.1
HTRA3	NM_001297559.3	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 7		NP_001284488.1
HTRA3	XM_011513596.4	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 7		XP_011511898.1
LOC105374373	XR_001741572.2	n.75+111C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA3	ENST00000307358.7	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 9	1	NM_053044.5	ENSP00000303766.2
HTRA3	ENST00000382512.3	c.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 7	1		ENSP00000371952.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28G>C (p.A10P) alteration is located in exon 1 (coding exon 1) of the HTRA3 gene. This alteration results from a G to C substitution at nucleotide position 28, causing the alanine (A) at amino acid position 10 to be replaced by a proline (P). 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	0.17
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.43	T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.14
Sift	Benign	0.26	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0010	B;B
Vest4		0.26
MutPred		0.41		Loss of MoRF binding (P = 0.0603);Loss of MoRF binding (P = 0.0603);
MVP		0.59
MPC		1.2
ClinPred		0.037	T
GERP RS		1.1
Varity_R		0.079
gMVP		0.63

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.

Other links and lift over

hg19: chr4-8271723;