10-122461664-G-T

Variant names:

• chr10-122461664-G-T
• rs761008513
• NM_002775.5:c.12G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_002775.5(HTRA1):​c.12G>T​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,312,120 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.295
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 10-122461664-G-T is Benign according to our data. Variant chr10-122461664-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 877206.
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000203 (30/147686) while in subpopulation NFE AF = 0.000347 (23/66194). AF 95% confidence interval is 0.000237. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.12G>T	p.Pro4Pro	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.12G>T	p.Pro4Pro	synonymous	Exon 1 of 9	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.12G>T	p.Pro4Pro	synonymous	Exon 1 of 9	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.12G>T	p.Pro4Pro	synonymous	Exon 1 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.000203 AC: 30 AN: 147686 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000347

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000133 AC: 10 AN: 75390 AF XY: 0.000162

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: 0.000374

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 280 AN: 1164434 Hom.: 1 Cov.: 29 AF XY: 0.000230 AC XY: 132 AN XY: 573644

African (AFR) AF: 0.00 AC: 0 AN: 22026

American (AMR) AF: 0.00 AC: 0 AN: 21936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16812

East Asian (EAS) AF: 0.00 AC: 0 AN: 16252

South Asian (SAS) AF: 0.00 AC: 0 AN: 69078

European-Finnish (FIN) AF: 0.000225 AC: 5 AN: 22212

Middle Eastern (MID) AF: 0.000327 AC: 1 AN: 3058

European-Non Finnish (NFE) AF: 0.000282 AC: 268 AN: 949246

Other (OTH) AF: 0.000137 AC: 6 AN: 43814

GnomAD4 genome AF: 0.000203 AC: 30 AN: 147686 Hom.: 0 Cov.: 32 AF XY: 0.000167 AC XY: 12 AN XY: 71854

African (AFR) AF: 0.0000975 AC: 4 AN: 41010

American (AMR) AF: 0.0000672 AC: 1 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000221 AC: 2 AN: 9032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000347 AC: 23 AN: 66194

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.7
DANN	Benign	0.95
PhyloP100		-0.29
PromoterAI		0.085	Neutral
Mutation Taster		=100/0	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: rs761008513; hg19: chr10-124221180;