10-122461813-A-T

Variant summary

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

The NM_002775.5(HTRA1):c.161A>T(p.Glu54Val) 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. 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. E54A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480

Genes affected

HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

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=0.08322474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.161A>T	p.Glu54Val	missense_variant	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.161A>T	p.Glu54Val	missense_variant	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.154+3104A>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.026
Sift	Benign	0.44	T
Sift4G	Benign	0.14	T
Polyphen		0.030	B
Vest4		0.14
MutPred		0.37		Loss of catalytic residue at E54 (P = 0.1219);
MVP		0.57
MPC		0.62
ClinPred		0.071	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.44

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: rs11538141; hg19: chr10-124221329;