10-122461166-T-C

Variant names:

• chr10-122461166-T-C
• rs2672598
• ENST00000648167.1:c.154+2457T>C

Variant summary

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

The ENST00000648167.1(HTRA1):​c.154+2457T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,074 control chromosomes in the GnomAD database, including 18,708 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 0.49 (18708 hom., cov: 34)
• Consequence: HTRA1 ENST00000648167.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80
• Publications: 22 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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-AS1 (HGNC:58122):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648167.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000648167.1		c.154+2457T>C		intron	N/A	ENSP00000498033.1	A0A3B3IU24
	HTRA1-AS1	ENST00000650300.1		n.218A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74590 AN: 151966 Hom.: 18677 Cov.: 34

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.491 AC: 74668 AN: 152074 Hom.: 18708 Cov.: 34 AF XY: 0.495 AC XY: 36821 AN XY: 74344

African (AFR) AF: 0.421 AC: 17469 AN: 41506

American (AMR) AF: 0.482 AC: 7384 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1825 AN: 3468

East Asian (EAS) AF: 0.709 AC: 3638 AN: 5128

South Asian (SAS) AF: 0.515 AC: 2486 AN: 4828

European-Finnish (FIN) AF: 0.607 AC: 6425 AN: 10588

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.498 AC: 33844 AN: 67936

Other (OTH) AF: 0.492 AC: 1041 AN: 2116

Alfa AF: 0.497 Hom.: 11322

Bravo AF: 0.482

Asia WGS AF: 0.584 AC: 2020 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.33
PhyloP100		-1.8
PromoterAI		-0.013	Neutral

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2672598;

hg19: chr10-124220682;