Genetic Variant ENST00000550683.5:c.-22C>T (chr12-51912411-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000550683.5(ACVRL1):c.-22C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,581,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ACVRL1
ENST00000550683.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.56

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

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550683.5. 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.-5-59C>T	intron	N/A	NP_000011.2	P37023
ACVRL1	NM_001077401.2		c.-64C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001070869.1	A0A0S2Z310
ACVRL1	NM_001406489.1		c.-64C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001393418.1	H3BTZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACVRL1	ENST00000550683.5	TSL:1	c.-22C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000447884.1	G3V1W8
ACVRL1	ENST00000550683.5	TSL:1	c.-22C>T	5_prime_UTR	Exon 1 of 9	ENSP00000447884.1	G3V1W8
ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.-5-59C>T	intron	N/A	ENSP00000373574.4	P37023

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

247206

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.0000642

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1429050

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

712766

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32750

American (AMR)

AF:

0.0000225

AC:

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

1083030

Other (OTH)

AF:

0.0000169

AC:

AN:

59254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Telangiectasia, hereditary hemorrhagic, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.0

(source)

DANN

Benign

0.64

PhyloP100

-1.6

PromoterAI

-0.13

Neutral

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over