10-122461660-T-C

Variant names:

• chr10-122461660-T-C
• rs1331849764
• NM_002775.5:c.8T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002775.5(HTRA1):​c.8T>C​(p.Ile3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000859 in 1,164,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.63
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037106514).

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.8T>C	p.Ile3Thr	missense	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.8T>C	p.Ile3Thr	missense	Exon 1 of 9	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.8T>C	p.Ile3Thr	missense	Exon 1 of 9	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.8T>C	p.Ile3Thr	missense	Exon 1 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.59e-7 AC: 1 AN: 1164750 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 573896

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

African (AFR) AF: 0.0000454 AC: 1 AN: 22004

American (AMR) AF: 0.00 AC: 0 AN: 21956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16808

East Asian (EAS) AF: 0.00 AC: 0 AN: 16198

South Asian (SAS) AF: 0.00 AC: 0 AN: 69216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 949402

Other (OTH) AF: 0.00 AC: 0 AN: 43864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.7
DANN	Benign	0.73
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.48	N
REVEL	Benign	0.16
Sift	Benign	0.78	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.18		Gain of phosphorylation at I3 (P = 0.0241)
MVP		0.44
MPC		0.64
ClinPred		0.026	T
GERP RS		-1.4
PromoterAI		-0.089	Neutral
Varity_R		0.034
gMVP		0.40
Mutation Taster		=95/5	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: rs1331849764; hg19: chr10-124221176;