Genetic Variant HTRA1:p.Leu14_Leu16dup (chr10-122461681-C-CGCTGCTGCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_002775.5(HTRA1):c.40_48dupCTGCTGCTG(p.Leu14_Leu16dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000862 in 1,159,658 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

HTRA1
NM_002775.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0930

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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
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: Orphanet, Ambry Genetics

HTRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_002775.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002775.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	NM_002775.5	MANE Select	c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	NP_002766.1	Q92743

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000357980.3	Q92743
HTRA1	ENST00000869938.1		c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000539997.1
HTRA1	ENST00000962536.1		c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000862

AC:

AN:

1159658

Hom.:

Cov.:

AF XY:

0.00000701

AC XY:

AN XY:

571006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22028

American (AMR)

AF:

0.00

AC:

AN:

21694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16742

East Asian (EAS)

AF:

0.00

AC:

AN:

16222

South Asian (SAS)

AF:

0.00

AC:

AN:

67520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3054

European-Non Finnish (NFE)

AF:

0.0000106

AC:

AN:

946594

Other (OTH)

AF:

0.00

AC:

AN:

43654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.093

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-122461681-CGCTGCT-CGCTGCTGCTGCTGCT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over