NM_002775.5:c.472+12644A>T

Variant names:

• chr10-122474768-A-T
• rs2672591
• NM_002775.5:c.472+12644A>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+12644A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 151,848 control chromosomes in the GnomAD database, including 21,238 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 (21238 hom., cov: 31)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.630
• Publications: 3 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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics

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 (AFR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002775.5. 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
	HTRA1	NM_002775.5	MANE Select	c.472+12644A>T		intron	N/A	NP_002766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.472+12644A>T		intron	N/A	ENSP00000357980.3
	HTRA1	ENST00000869938.1		c.472+12644A>T		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.472+12644A>T		intron	N/A	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79188 AN: 151730 Hom.: 21210 Cov.: 31

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.522 AC: 79266 AN: 151848 Hom.: 21238 Cov.: 31 AF XY: 0.520 AC XY: 38565 AN XY: 74202

African (AFR) AF: 0.633 AC: 26194 AN: 41382

American (AMR) AF: 0.455 AC: 6943 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3062 AN: 5148

South Asian (SAS) AF: 0.459 AC: 2200 AN: 4798

European-Finnish (FIN) AF: 0.476 AC: 5009 AN: 10524

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32767 AN: 67950

Other (OTH) AF: 0.503 AC: 1060 AN: 2106

Alfa AF: 0.541 Hom.: 12723

Bravo AF: 0.527

Asia WGS AF: 0.544 AC: 1889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.12
DANN	Benign	0.88
PhyloP100		-0.63
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: rs2672591; hg19: chr10-124234284;