10-122464428-C-T

Variant names:

• chr10-122464428-C-T
• rs2248799
• NM_002775.5:c.472+2304C>T

Variant summary

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

The NM_002775.5(HTRA1):​c.472+2304C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,914 control chromosomes in the GnomAD database, including 20,513 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 0.52 (20513 hom., cov: 31)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 12 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: 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.472+2304C>T		intron_variant	Intron 1 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.472+2304C>T		intron_variant	Intron 1 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+5719C>T		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78175 AN: 151796 Hom.: 20486 Cov.: 31

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.504

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

GnomAD4 genome AF: 0.515 AC: 78259 AN: 151914 Hom.: 20513 Cov.: 31 AF XY: 0.514 AC XY: 38153 AN XY: 74232

African (AFR) AF: 0.579 AC: 23988 AN: 41416

American (AMR) AF: 0.464 AC: 7092 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3470

East Asian (EAS) AF: 0.748 AC: 3842 AN: 5136

South Asian (SAS) AF: 0.483 AC: 2326 AN: 4814

European-Finnish (FIN) AF: 0.471 AC: 4956 AN: 10532

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33085 AN: 67960

Other (OTH) AF: 0.500 AC: 1056 AN: 2110

Alfa AF: 0.500 Hom.: 41390

Bravo AF: 0.518

Asia WGS AF: 0.607 AC: 2109 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.6
DANN	Benign	0.35
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2248799; hg19: chr10-124223944;