10-122461686-C-T

Variant names:

• chr10-122461686-C-T
• rs996483189
• NM_002775.5:c.34C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_002775.5(HTRA1):​c.34C>T​(p.Leu12Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,156,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.567
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-122461686-C-T is Benign according to our data. Variant chr10-122461686-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 871446.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=0.567 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.34C>T	p.Leu12Leu	synonymous_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.34C>T	p.Leu12Leu	synonymous_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+2977C>T		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000692 AC: 8 AN: 1156604 Hom.: 0 Cov.: 31 AF XY: 0.0000123 AC XY: 7 AN XY: 569508

African (AFR) AF: 0.00 AC: 0 AN: 21890

American (AMR) AF: 0.00 AC: 0 AN: 21522

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 16282

South Asian (SAS) AF: 0.000118 AC: 8 AN: 67588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 944516

Other (OTH) AF: 0.00 AC: 0 AN: 43490

GnomAD4 genome Cov.: 32

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.00133

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.6
DANN	Benign	0.95
PhyloP100		0.57
PromoterAI		-0.0064	Neutral

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: rs996483189; hg19: chr10-124221202;