chr10-122461681-C-CGCTGCTGCT

Variant names:

• chr10-122461681-C-CGCTGCTGCT
• rs746547640
• NM_002775.5:c.40_48dupCTGCTGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_002775.5(HTRA1):​c.40_48dupCTGCTGCTG​(p.Leu14_Leu16dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000862 in 1,159,658 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: HTRA1 NM_002775.5 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002775.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.40_48dupCTGCTGCTG	p.Leu14_Leu16dup	conservative_inframe_insertion	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+2983_154+2991dupCTGCTGCTG		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000862 AC: 10 AN: 1159658 Hom.: 0 Cov.: 30 AF XY: 0.00000701 AC XY: 4 AN XY: 571006

African (AFR) AF: 0.00 AC: 0 AN: 22028

American (AMR) AF: 0.00 AC: 0 AN: 21694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16742

East Asian (EAS) AF: 0.00 AC: 0 AN: 16222

South Asian (SAS) AF: 0.00 AC: 0 AN: 67520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3054

European-Non Finnish (NFE) AF: 0.0000106 AC: 10 AN: 946594

Other (OTH) AF: 0.00 AC: 0 AN: 43654

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.093

Splicing

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

Other links and lift over

dbSNP: rs746547640; hg19: chr10-124221197;