10-122461711-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002775.5(HTRA1):c.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,297,084 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (85 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (459 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.298

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015049279).
• BP6: Variant 10-122461711-C-T is Benign according to our data. Variant chr10-122461711-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122461711-C-T is described in Lovd as [Benign]. Variant chr10-122461711-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.59C>T	p.Ala20Val	missense_variant	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.59C>T	p.Ala20Val	missense_variant	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.154+3002C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1739 AN: 147886 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.000587

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.00445

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00464

Gnomad OTH AF: 0.0128

GnomAD3 exomes AF: 0.0212 AC: 1513 AN: 71438 Hom.: 59 AF XY: 0.0210 AC XY: 862 AN XY: 41100

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.0351

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00935 AC: 10745 AN: 1149088 Hom.: 459 Cov.: 31 AF XY: 0.0102 AC XY: 5779 AN XY: 565652

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00416

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0117 AC: 1737 AN: 147996 Hom.: 85 Cov.: 32 AF XY: 0.0130 AC XY: 936 AN XY: 72122

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.000587

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.0392

Gnomad4 FIN AF: 0.00445

Gnomad4 NFE AF: 0.00464

Gnomad4 OTH AF: 0.0126

Alfa AF: 0.00648 Hom.: 4

Bravo AF: 0.0125

ExAC AF: 0.0165 AC: 448

Asia WGS AF: 0.0670 AC: 203 AN: 3010

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Macular degeneration Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

CARASIL syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.16
Sift	Benign	0.63	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.045
MPC		0.51
ClinPred		0.0038	T
GERP RS		0.42
Varity_R		0.062
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs369149111; hg19: chr10-124221227; COSMIC: COSV64564485; COSMIC: COSV64564485;