10-122461729-G-A

Position:

• chr10-122461729-G-A

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.77G>A​(p.Arg26Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,181,636 control chromosomes in the GnomAD database, including 85 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (53 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.228

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=0.0018782914).
• BP6: Variant 10-122461729-G-A is Benign according to our data. Variant chr10-122461729-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 299045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122461729-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.77G>A	p.Arg26Gln	missense_variant	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.77G>A	p.Arg26Gln	missense_variant	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.154+3020G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1924 AN: 147674 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00652

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000271

Gnomad OTH AF: 0.00837

GnomAD3 exomes AF: 0.00407 AC: 185 AN: 45490 Hom.: 1 AF XY: 0.00479 AC XY: 132 AN XY: 27552

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.000238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00189 AC: 1950 AN: 1033854 Hom.: 53 Cov.: 30 AF XY: 0.00202 AC XY: 1019 AN XY: 503432

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.00501

GnomAD4 genome AF: 0.0131 AC: 1929 AN: 147782 Hom.: 32 Cov.: 32 AF XY: 0.0127 AC XY: 913 AN XY: 72018

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.00645

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000271

Gnomad4 OTH AF: 0.00828

Alfa AF: 0.000141 Hom.: 0

ExAC AF: 0.00461 AC: 90

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.18
Sift	Benign	0.29	T
Sift4G	Benign	0.32	T
Polyphen		0.25	B
Vest4		0.073
MVP		0.86
MPC		0.59
ClinPred		0.0072	T
GERP RS		2.9
Varity_R		0.093
gMVP		0.38

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: rs190036021; hg19: chr10-124221245;