Genetic Variant HTRA1:c.1275-36C>A (chr10-122514155-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002775.5(HTRA1):c.1275-36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HTRA1
NM_002775.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.246

Publications

0 publications found

Variant links:

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

HTRA1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.1275-36C>A		intron_variant	Intron 8 of 8	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTRA1	ENST00000368984.8 link	c.1275-36C>A	intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.957-36C>A	intron_variant	Intron 8 of 8			ENSP00000498033.1	A0A3B3IU24
HTRA1	ENST00000420892.1 link	c.498-36C>A	intron_variant	Intron 5 of 5	2		ENSP00000412676.1	H0Y7G9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33302

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5068

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105560

Other (OTH)

AF:

0.00

AC:

AN:

60026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.0

(source)

DANN

Benign

0.48

PhyloP100

-0.25

BranchPoint Hunter

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over