NM_002775.5:c.33_34insT

Variant names:

• chr10-122461685-G-GT
• rs541533723
• NM_002775.5:c.33_34insT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1 BS1 BS2

The NM_002775.5(HTRA1):​c.33_34insT​(p.Leu12SerfsTer157) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,303,744 control chromosomes in the GnomAD database, including 10 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (9 hom.)
• Consequence: HTRA1 NM_002775.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.567
• Publications: 2 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 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00184 (272/147568) while in subpopulation EAS AF = 0.0277 (141/5092). AF 95% confidence interval is 0.024. There are 1 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.33_34insT	p.Leu12SerfsTer157	frameshift_variant	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.33_34insT	p.Leu12SerfsTer157	frameshift_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+2976_154+2977insT		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 274 AN: 147464 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000337

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000454

Gnomad OTH AF: 0.000493

GnomAD2 exomes AF: 0.000188 AC: 12 AN: 63742 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00446

Gnomad FIN exome AF: 0.000518

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000908 AC: 1050 AN: 1156176 Hom.: 9 Cov.: 31 AF XY: 0.000889 AC XY: 506 AN XY: 569282

African (AFR) AF: 0.00 AC: 0 AN: 21888

American (AMR) AF: 0.000139 AC: 3 AN: 21516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16524

East Asian (EAS) AF: 0.0314 AC: 510 AN: 16264

South Asian (SAS) AF: 0.000118 AC: 8 AN: 67528

European-Finnish (FIN) AF: 0.00930 AC: 202 AN: 21732

Middle Eastern (MID) AF: 0.000330 AC: 1 AN: 3030

European-Non Finnish (NFE) AF: 0.000225 AC: 212 AN: 944262

Other (OTH) AF: 0.00262 AC: 114 AN: 43432

GnomAD4 genome AF: 0.00184 AC: 272 AN: 147568 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 172 AN XY: 71842

African (AFR) AF: 0.0000487 AC: 2 AN: 41100

American (AMR) AF: 0.000336 AC: 5 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.0277 AC: 141 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0104 AC: 93 AN: 8954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000454 AC: 30 AN: 66104

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.000918 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=130/70	disease causing (fs/PTC)

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: rs541533723; hg19: chr10-124221201;