Genetic Variant ENSG00000285955:n.588G>C (chr10-122459759-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000650300.1(ENSG00000285955):n.588G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 151,962 control chromosomes in the GnomAD database, including 4,464 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4464 hom., cov: 31)

Consequence

ENSG00000285955
ENST00000650300.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.405

Publications

63 publications found

Variant links:

Genes affected

ENSG00000285955 (HGNC:58122):

ENSG00000285955 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
HTRA1-AS1	XR_946382.3 link	n.610G>C	non_coding_transcript_exon_variant	Exon 2 of 3
HTRA1-AS1	XR_946383.3 link	n.588G>C	non_coding_transcript_exon_variant	Exon 2 of 4
HTRA1-AS1	XR_946384.3 link	n.588G>C	non_coding_transcript_exon_variant	Exon 2 of 4
HTRA1-AS1	XR_946385.3 link	n.588G>C	non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285955	ENST00000650300.1 link	n.588G>C		non_coding_transcript_exon_variant	Exon 2 of 3
HTRA1	ENST00000648167.1 link	c.154+1050C>G		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35892

AN:

151844

Hom.:

4456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.288

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.208

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.237

AC:

35941

AN:

151962

Hom.:

4464

Cov.:

AF XY:

0.239

AC XY:

17777

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.235

AC:

9761

AN:

41450

American (AMR)

AF:

0.232

AC:

3543

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

722

AN:

3466

East Asian (EAS)

AF:

0.424

AC:

2175

AN:

5130

South Asian (SAS)

AF:

0.319

AC:

1532

AN:

4806

European-Finnish (FIN)

AF:

0.236

AC:

2492

AN:

10568

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.219

AC:

14896

AN:

67948

Other (OTH)

AF:

0.236

AC:

498

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1338

2676

4015

5353

6691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.149

Hom.:

298

Bravo

AF:

0.239

Asia WGS

AF:

0.371

AC:

1285

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.84

(source)

DANN

Benign

0.41

PhyloP100

-0.41

Splicing

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