rs996483189

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, 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: 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 VariationId is 871446.
• BP7: Synonymous conserved (PhyloP=0.567 with no splicing effect.

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.34C>T	p.Leu12Leu	synonymous	Exon 1 of 9	NP_002766.1	Q92743

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.34C>T	p.Leu12Leu	synonymous	Exon 1 of 9	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.34C>T	p.Leu12Leu	synonymous	Exon 1 of 9	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.34C>T	p.Leu12Leu	synonymous	Exon 1 of 9	ENSP00000632595.1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

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;