Genetic Variant NM_001111067.4:c.1124G>A (chr2-157761020-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-157761020-C-G is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4 link	c.1124G>A	p.Arg375His	missense_variant	Exon 9 of 11	ENST00000434821.7	NP_001104537.1	Q04771D3DPA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7 link	c.1124G>A	p.Arg375His	missense_variant	Exon 9 of 11	1	NM_001111067.4	ENSP00000405004.1		Q04771

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg375 amino acid residue in ACVR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19085907, 22977237, 34854557). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with ACVR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 375 of the ACVR1 protein (p.Arg375His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;D;D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

.;.;D;.

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.1

L;L;L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.28

MutPred

0.66

Gain of disorder (P = 0.1198);Gain of disorder (P = 0.1198);Gain of disorder (P = 0.1198);Gain of disorder (P = 0.1198);

MVP

0.79

MPC

1.6

ClinPred

0.99

GERP RS

5.7

Varity_R

0.88

gMVP

0.59

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over