NM_002775.5:c.46_48delCTG

Variant names:

• chr10-122461681-CGCT-C
• rs746547640
• NM_002775.5:c.46_48delCTG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_002775.5(HTRA1):​c.46_48delCTG​(p.Leu16del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,263,218 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: 𝑓 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (0 hom.)
• Consequence: HTRA1 NM_002775.5 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.892
• 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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002775.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.46_48delCTG	p.Leu16del	conservative_inframe_deletion	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.46_48delCTG	p.Leu16del	conservative_inframe_deletion	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+2989_154+2991delCTG		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.0000543 AC: 8 AN: 147438 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000224

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000907

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00674 AC: 448 AN: 66442 AF XY: 0.00648

Gnomad AFR exome AF: 0.00750

Gnomad AMR exome AF: 0.00858

Gnomad ASJ exome AF: 0.00454

Gnomad EAS exome AF: 0.0140

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00352 AC: 3933 AN: 1115780 Hom.: 0 AF XY: 0.00381 AC XY: 2089 AN XY: 547922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00310 AC: 66 AN: 21290

American (AMR) AF: 0.0101 AC: 207 AN: 20418

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 97 AN: 16004

East Asian (EAS) AF: 0.00887 AC: 135 AN: 15220

South Asian (SAS) AF: 0.00971 AC: 604 AN: 62196

European-Finnish (FIN) AF: 0.00982 AC: 206 AN: 20970

Middle Eastern (MID) AF: 0.00553 AC: 16 AN: 2894

European-Non Finnish (NFE) AF: 0.00260 AC: 2375 AN: 914884

Other (OTH) AF: 0.00542 AC: 227 AN: 41904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000543 AC: 8 AN: 147438 Hom.: 0 Cov.: 32 AF XY: 0.0000558 AC XY: 4 AN XY: 71716

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40992

American (AMR) AF: 0.00 AC: 0 AN: 14850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000224 AC: 2 AN: 8920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000907 AC: 6 AN: 66130

Other (OTH) AF: 0.00 AC: 0 AN: 2026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89
Mutation Taster		=75/25	polymorphism

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: rs746547640; hg19: chr10-124221197; COSMIC: COSV100934805; COSMIC: COSV100934805;