dbSNP rs115378744: ACVRL1:c.1246+9C>T (chr12-51916242-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000020.3(ACVRL1):c.1246+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,228 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene ACVRL1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0089 ( 21 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 20 hom. )

Consequence

ACVRL1
NM_000020.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.58

Publications

0 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, ClinGen, Labcorp Genetics (formerly Invitae), 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

Specifications for ACVRL1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-51916242-C-T is Benign according to our data. Variant chr12-51916242-C-T is described in ClinVar as Benign. ClinVar VariationId is 254708.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 = 0.00893 (1359/152240) while in subpopulation AFR AF = 0.0312 (1297/41536). AF 95% confidence interval is 0.0298. There are 21 homozygotes in GnomAd4. There are 640 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD 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	Effect	Exon Rank	Protein	UniProt
ACVRL1	NM_000020.3	MANE Select	c.1246+9C>T	intron	N/A	NP_000011.2	P37023
ACVRL1	NM_001077401.2		c.1246+9C>T	intron	N/A	NP_001070869.1	A0A0S2Z310
ACVRL1	NM_001406487.1		c.1246+9C>T	intron	N/A	NP_001393416.1	A0A0S2Z310

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1246+9C>T	intron	N/A	ENSP00000373574.4	P37023
ACVRL1	ENST00000550683.5	TSL:1	c.1288+9C>T	intron	N/A	ENSP00000447884.1	G3V1W8
ACVRL1	ENST00000551576.6	TSL:1	c.1246+9C>T	intron	N/A	ENSP00000455848.2	P37023

Frequencies

GnomAD3 genomes

AF:

0.00890

AC:

1354

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00230

AC:

570

AN:

247898

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.0324

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000904

AC:

1321

AN:

1460988

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

566

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.0322

AC:

1076

AN:

33450

American (AMR)

AF:

0.00152

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111694

Other (OTH)

AF:

0.00222

AC:

134

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00893

AC:

1359

AN:

152240

Hom.:

Cov.:

AF XY:

0.00860

AC XY:

640

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0312

AC:

1297

AN:

41536

American (AMR)

AF:

0.00274

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00434

Hom.:

Bravo

AF:

0.00994

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Telangiectasia, hereditary hemorrhagic, type 2 (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.38

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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