rs11538692

Positions:

• chr2-74531040-C-T

Variant summary

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

The NM_013247.5(HTRA2):​c.841C>T​(p.Pro281Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P281P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA2 NM_013247.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12

Genes affected

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

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=0.21836704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA2	NM_013247.5	c.841C>T	p.Pro281Ser	missense_variant	3/8	ENST00000258080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA2	ENST00000258080.8	c.841C>T	p.Pro281Ser	missense_variant	3/8	1	NM_013247.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	-0.57	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.81	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.60	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.77	P;.
Vest4		0.18
MutPred		0.30		Gain of phosphorylation at P281 (P = 0.0336);.;
MVP		0.93
MPC		1.9
ClinPred		0.86	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.74

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

Other links and lift over

dbSNP: rs11538692; hg19: chr2-74758167;