chr12-51919160-T-C

Variant names:

• chr12-51919160-T-C
• rs706815
• NM_000020.3:c.1377+45T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001406488.1(ACVRL1):​c.1422T>C​(p.His474His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,612,628 control chromosomes in the GnomAD database, including 56,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8354 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48471 hom.)
• Consequence: ACVRL1 NM_001406488.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.824
• Publications: 9 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-51919160-T-C is Benign according to our data. Variant chr12-51919160-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406488.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	NM_000020.3	MANE Select	c.1377+45T>C		intron	N/A	NP_000011.2
	ACVRL1	NM_001406488.1		c.1422T>C	p.His474His	synonymous	Exon 9 of 9	NP_001393417.1
	ACVRL1	NM_001406489.1		c.1422T>C	p.His474His	synonymous	Exon 8 of 8	NP_001393418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVRL1	ENST00000388922.9	TSL:1 MANE Select	c.1377+45T>C		intron	N/A	ENSP00000373574.4
	ACVRL1	ENST00000550683.5	TSL:1	c.1419+45T>C		intron	N/A	ENSP00000447884.1
	ACVRL1	ENST00000551576.6	TSL:1	c.1377+45T>C		intron	N/A	ENSP00000455848.2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47310 AN: 151594 Hom.: 8333 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.264 AC: 65716 AN: 248984 AF XY: 0.258

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.423

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.252 AC: 367933 AN: 1460916 Hom.: 48471 Cov.: 35 AF XY: 0.251 AC XY: 182227 AN XY: 726724

African (AFR) AF: 0.501 AC: 16776 AN: 33466

American (AMR) AF: 0.191 AC: 8522 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7514 AN: 26134

East Asian (EAS) AF: 0.436 AC: 17309 AN: 39672

South Asian (SAS) AF: 0.237 AC: 20424 AN: 86234

European-Finnish (FIN) AF: 0.237 AC: 12597 AN: 53230

Middle Eastern (MID) AF: 0.224 AC: 1290 AN: 5762

European-Non Finnish (NFE) AF: 0.240 AC: 267129 AN: 1111472

Other (OTH) AF: 0.271 AC: 16372 AN: 60352

GnomAD4 genome AF: 0.312 AC: 47370 AN: 151712 Hom.: 8354 Cov.: 32 AF XY: 0.309 AC XY: 22872 AN XY: 74122

African (AFR) AF: 0.491 AC: 20269 AN: 41272

American (AMR) AF: 0.224 AC: 3422 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 966 AN: 3462

East Asian (EAS) AF: 0.451 AC: 2317 AN: 5136

South Asian (SAS) AF: 0.234 AC: 1122 AN: 4804

European-Finnish (FIN) AF: 0.219 AC: 2318 AN: 10562

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16077 AN: 67906

Other (OTH) AF: 0.299 AC: 627 AN: 2098

Alfa AF: 0.263 Hom.: 2250

Bravo AF: 0.322

Asia WGS AF: 0.346 AC: 1200 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Telangiectasia, hereditary hemorrhagic, type 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.39
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs706815; hg19: chr12-52312944; COSMIC: COSV107485469; COSMIC: COSV107485469;