dbSNP rs77341011: ACVRL1:p.Ser110Ser (chr12-51913575-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_000020.3(ACVRL1):c.330G>A(p.Ser110Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,598,474 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 53 hom. )

Consequence

ACVRL1
NM_000020.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.297

Publications

2 publications found

Variant links:

Genes affected

ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

ACVRL1 Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
hereditary hemorrhagic telangiectasia
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACVRL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 12-51913575-G-A is Benign according to our data. Variant chr12-51913575-G-A is described in ClinVar as Benign. ClinVar VariationId is 212791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2069/152342) while in subpopulation AFR AF = 0.0407 (1692/41580). AF 95% confidence interval is 0.0391. There are 39 homozygotes in GnomAd4. There are 970 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000020.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACVRL1	NM_000020.3	MANE Select	c.330G>A	p.Ser110Ser	synonymous	Exon 4 of 10	NP_000011.2
ACVRL1	NM_001077401.2		c.330G>A	p.Ser110Ser	synonymous	Exon 3 of 9	NP_001070869.1
ACVRL1	NM_001406487.1		c.330G>A	p.Ser110Ser	synonymous	Exon 5 of 11	NP_001393416.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.330G>A	p.Ser110Ser	synonymous	Exon 4 of 10	ENSP00000373574.4
ACVRL1	ENST00000550683.5	TSL:1	c.372G>A	p.Ser124Ser	synonymous	Exon 3 of 9	ENSP00000447884.1
ACVRL1	ENST00000551576.6	TSL:1	c.330G>A	p.Ser110Ser	synonymous	Exon 5 of 11	ENSP00000455848.2

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2064

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00468

AC:

1099

AN:

234742

AF XY:

0.00383

show subpopulations

Gnomad AFR exome

AF:

0.0422

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.00175

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00419

GnomAD4 exome

AF:

0.00354

AC:

5113

AN:

1446132

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

2336

AN XY:

719834

show subpopulations

African (AFR)

AF:

0.0399

AC:

1333

AN:

33410

American (AMR)

AF:

0.00383

AC:

171

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26100

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39662

South Asian (SAS)

AF:

0.000442

AC:

AN:

86018

European-Finnish (FIN)

AF:

0.00192

AC:

AN:

39628

Middle Eastern (MID)

AF:

0.00251

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.00287

AC:

3189

AN:

1111714

Other (OTH)

AF:

0.00482

AC:

290

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

331

662

992

1323

1654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0136

AC:

2069

AN:

152342

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

970

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0407

AC:

1692

AN:

41580

American (AMR)

AF:

0.00784

AC:

120

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00303

AC:

206

AN:

68034

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

110

220

329

439

549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00900

Hom.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00232

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Telangiectasia, hereditary hemorrhagic, type 2 (5)

not specified (4)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.51

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.72

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over