2-157761020-C-T

Variant names:

• chr2-157761020-C-T
• rs387906590
• NM_001111067.4:c.1124G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5 BS2

The NM_001111067.4(ACVR1):​c.1124G>A​(p.Arg375His) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89
• Publications: 0 publications found

Genes affected

ACVR1 (HGNC:171): (activin A receptor type 1) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

ACVR1 Gene-Disease associations (from GenCC):

• fibrodysplasia ossificans progressiva

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-157761020-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 29596.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111067.4. 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
	ACVR1	NM_001111067.4	MANE Select	c.1124G>A	p.Arg375His	missense	Exon 9 of 11	NP_001104537.1
	ACVR1	NM_001105.5		c.1124G>A	p.Arg375His	missense	Exon 9 of 11	NP_001096.1
	ACVR1	NM_001347663.1		c.1124G>A	p.Arg375His	missense	Exon 9 of 11	NP_001334592.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1	ENST00000434821.7	TSL:1 MANE Select	c.1124G>A	p.Arg375His	missense	Exon 9 of 11	ENSP00000405004.1
	ACVR1	ENST00000263640.7	TSL:1	c.1124G>A	p.Arg375His	missense	Exon 9 of 11	ENSP00000263640.3
	ACVR1	ENST00000410057.6	TSL:1	c.1124G>A	p.Arg375His	missense	Exon 10 of 12	ENSP00000387127.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.66		Gain of disorder (P = 0.1198)
MVP		0.79
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.59
Mutation Taster		=37/63	disease causing

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: rs387906590; hg19: chr2-158617532; COSMIC: COSV99717598;