NM_002775.5:c.73T>A

Variant names:

• chr10-122461725-T-A
• rs1287832329
• NM_002775.5:c.73T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002775.5(HTRA1):​c.73T>A​(p.Ser25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000678 in 147,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S25F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 0 publications found

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]

HTRA1 Gene-Disease associations (from GenCC):

• CARASIL syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• genetic cerebral small vessel disease

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• HTRA1-related autosomal dominant cerebral small vessel disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06791744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.73T>A	p.Ser25Thr	missense_variant	Exon 1 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.73T>A	p.Ser25Thr	missense_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+3016T>A		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147568 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1045578 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 509890

African (AFR) AF: 0.00 AC: 0 AN: 19728

American (AMR) AF: 0.00 AC: 0 AN: 13100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13034

East Asian (EAS) AF: 0.00 AC: 0 AN: 13668

South Asian (SAS) AF: 0.00 AC: 0 AN: 45896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2546

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 884702

Other (OTH) AF: 0.00 AC: 0 AN: 37632

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147568 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71848

African (AFR) AF: 0.00 AC: 0 AN: 40922

American (AMR) AF: 0.00 AC: 0 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66282

Other (OTH) AF: 0.00 AC: 0 AN: 2032

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.1
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.13
Sift	Benign	0.47	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.20		Loss of helix (P = 0.0033);
MVP		0.68
MPC		0.46
ClinPred		0.032	T
GERP RS		-1.7
PromoterAI		0.078	Neutral
Varity_R		0.071
gMVP		0.42
Mutation Taster		=94/6	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: rs1287832329; hg19: chr10-124221241;