10-122462011-G-T

Position:

• chr10-122462011-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_002775.5(HTRA1):​c.359G>T​(p.Gly120Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G120D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.01

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 36) in uniprot entity HTRA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-122462011-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523572.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.359G>T	p.Gly120Val	missense_variant	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.359G>T	p.Gly120Val	missense_variant	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.154+3302G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.95		Loss of disorder (P = 0.0658);
MVP		0.66
MPC		1.6
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.84
gMVP		0.95

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: rs1554948318; hg19: chr10-124221527;