ENST00000650300.1:n.356C>T

Variant names:

• chr10-122461028-G-A
• rs11200638
• ENST00000650300.1:n.356C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000650300.1(ENSG00000285955):​n.356C>T 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 0.234 in 152,162 control chromosomes in the GnomAD database, including 4,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.23 (4399 hom., cov: 34)
• Consequence: ENSG00000285955 ENST00000650300.1 non_coding_transcript_exon
• Clinical Significance: risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: -0.125
• Publications: 294 publications found

Genes affected

ENSG00000285955 (HGNC:58122):

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1-AS1	XR_946382.3	n.378C>T		non_coding_transcript_exon_variant	Exon 1 of 3
HTRA1-AS1	XR_946383.3	n.356C>T		non_coding_transcript_exon_variant	Exon 1 of 4
HTRA1-AS1	XR_946384.3	n.356C>T		non_coding_transcript_exon_variant	Exon 1 of 4
HTRA1-AS1	XR_946385.3	n.356C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285955	ENST00000650300.1	n.356C>T		non_coding_transcript_exon_variant	Exon 1 of 3
HTRA1	ENST00000648167.1	c.154+2319G>A		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35620 AN: 152042 Hom.: 4389 Cov.: 34

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.238

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

GnomAD4 genome AF: 0.234 AC: 35666 AN: 152162 Hom.: 4399 Cov.: 34 AF XY: 0.237 AC XY: 17634 AN XY: 74384

African (AFR) AF: 0.234 AC: 9738 AN: 41542

American (AMR) AF: 0.230 AC: 3521 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3468

East Asian (EAS) AF: 0.424 AC: 2176 AN: 5130

South Asian (SAS) AF: 0.316 AC: 1528 AN: 4832

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10596

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14721 AN: 67968

Other (OTH) AF: 0.235 AC: 498 AN: 2116

Alfa AF: 0.222 Hom.: 4659

Bravo AF: 0.236

Asia WGS AF: 0.369 AC: 1277 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Age related macular degeneration 7 Other:1

Feb 18, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Susceptibility to neovascular type of age-related macular degeneration Other:1

Feb 18, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.4
DANN	Benign	0.87
PhyloP100		-0.13

Splicing

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

Other links and lift over

dbSNP: rs11200638; hg19: chr10-124220544; COSMIC: COSV64564929;