NM_002775.5:c.62C>T

Variant names:

• chr10-122461714-C-T
• rs745597966
• NM_002775.5:c.62C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002775.5(HTRA1):​c.62C>T​(p.Ser21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,294,562 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.183
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• 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: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.096105516).

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.62C>T	p.Ser21Leu	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.62C>T	p.Ser21Leu	missense	Exon 1 of 9	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.62C>T	p.Ser21Leu	missense	Exon 1 of 9	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.62C>T	p.Ser21Leu	missense	Exon 1 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147894 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000422 AC: 3 AN: 71008 AF XY: 0.0000490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 15 AN: 1146560 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 7 AN XY: 564418

African (AFR) AF: 0.00 AC: 0 AN: 21644

American (AMR) AF: 0.00 AC: 0 AN: 21044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16070

East Asian (EAS) AF: 0.00 AC: 0 AN: 15036

South Asian (SAS) AF: 0.000179 AC: 12 AN: 67136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2990

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 938996

Other (OTH) AF: 0.0000700 AC: 3 AN: 42878

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 148002 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72110

African (AFR) AF: 0.00 AC: 0 AN: 41170

American (AMR) AF: 0.00 AC: 0 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66354

Other (OTH) AF: 0.00 AC: 0 AN: 2056

ExAC AF: 0.0000754 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.18
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.49	N
REVEL	Benign	0.13
Sift	Benign	0.29	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.24		Loss of loop (P = 0.0112)
MVP		0.69
MPC		0.45
ClinPred		0.037	T
GERP RS		0.81
PromoterAI		0.012	Neutral
Varity_R		0.054
gMVP		0.44
Mutation Taster		=88/12	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: rs745597966; hg19: chr10-124221230;