rs11538140

Variant names:

• chr10-122512012-C-T
• rs11538140
• NM_002775.5:c.1221C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-122512012-C-T
• chr10-122512012-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002775.5(HTRA1):​c.1221C>T​(p.Asp407Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,950 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.819
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 10-122512012-C-T is Benign according to our data. Variant chr10-122512012-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 299052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.819 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00311 (473/152236) while in subpopulation EAS AF = 0.0165 (85/5162). AF 95% confidence interval is 0.0136. There are 2 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1221C>T	p.Asp407Asp	synonymous	Exon 8 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.1221C>T	p.Asp407Asp	synonymous	Exon 8 of 9	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.1224C>T	p.Asp408Asp	synonymous	Exon 8 of 9	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.1215C>T	p.Asp405Asp	synonymous	Exon 8 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 152118 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00397 AC: 997 AN: 251446 AF XY: 0.00369

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0146

Gnomad FIN exome AF: 0.00721

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00346 AC: 5057 AN: 1461714 Hom.: 18 Cov.: 30 AF XY: 0.00333 AC XY: 2425 AN XY: 727178

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00235 AC: 105 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.0173 AC: 686 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86244

European-Finnish (FIN) AF: 0.00805 AC: 430 AN: 53412

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.00320 AC: 3554 AN: 1111898

Other (OTH) AF: 0.00363 AC: 219 AN: 60370

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152236 Hom.: 2 Cov.: 31 AF XY: 0.00320 AC XY: 238 AN XY: 74430

African (AFR) AF: 0.000626 AC: 26 AN: 41538

American (AMR) AF: 0.00196 AC: 30 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0165 AC: 85 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00354 Hom.: 4

Bravo AF: 0.00280

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Macular degeneration (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		-0.82
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11538140; hg19: chr10-124271528;