Variant 10-122461681-C-CGCT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBS1_Supporting

The NM_002775.5(HTRA1):c.46_48dup(p.Leu16dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000987 in 1,307,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

HTRA1
NM_002775.5 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0930

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_002775.5. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0004 (59/147554) while in subpopulation AFR AF= 0.00124 (51/41106). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5 linkuse as main transcript	c.46_48dup	p.Leu16dup	inframe_insertion	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8 linkuse as main transcript	c.46_48dup	p.Leu16dup	inframe_insertion	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1 linkuse as main transcript	c.154+2989_154+2991dup		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000393

AC:

AN:

147452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000907

Gnomad OTH

AF:

0.000494

GnomAD3 exomes

AF:

0.0000903

AC:

AN:

66442

Hom.:

AF XY:

0.0000527

AC XY:

AN XY:

37970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000286

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000703

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000425

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000604

AC:

AN:

1159602

Hom.:

Cov.:

AF XY:

0.0000508

AC XY:

AN XY:

570978

show subpopulations

Gnomad4 AFR exome

AF:

0.00118

Gnomad4 AMR exome

AF:

0.000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000889

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000349

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000400

AC:

AN:

147554

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

AN XY:

71842

show subpopulations

Gnomad4 AFR

AF:

0.00124

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000907

Gnomad4 OTH

AF:

0.000488

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This variant, c.46_48dup, results in the insertion of 1 amino acid(s) of the HTRA1 protein (p.Leu16dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770388445, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HTRA1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over