dbSNP rs115359066: ACVR1C:p.Val487Ile (chr2-157533941-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_145259.3(ACVR1C):c.1459G>A(p.Val487Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,583,276 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.736

Variant links:

Genes affected

ACVR1C (HGNC:18123): (activin A receptor type 1C) ACVR1C is a type I receptor for the TGFB (see MIM 190180) family of signaling molecules. Upon ligand binding, type I receptors phosphorylate cytoplasmic SMAD transcription factors, which then translocate to the nucleus and interact directly with DNA or in complex with other transcription factors (Bondestam et al., 2001 [PubMed 12063393]).[supplied by OMIM, Mar 2008]

ACVR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041641295).

BP6

Variant 2-157533941-C-T is Benign according to our data. Variant chr2-157533941-C-T is described in ClinVar as [Benign]. Clinvar id is 3049447.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1C	NM_145259.3 link	c.1459G>A	p.Val487Ile	missense_variant	Exon 9 of 9	ENST00000243349.13	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2 link	c.1309G>A	p.Val437Ile	missense_variant	Exon 9 of 9		NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2 link	c.1219G>A	p.Val407Ile	missense_variant	Exon 8 of 8		NP_001104502.1	Q8NER5-3
ACVR1C	NM_001111033.2 link	c.988G>A	p.Val330Ile	missense_variant	Exon 7 of 7		NP_001104503.1	Q8NER5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR1C	ENST00000243349.13 link	c.1459G>A	p.Val487Ile	missense_variant	Exon 9 of 9	1	NM_145259.3	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7 link	c.1309G>A	p.Val437Ile	missense_variant	Exon 9 of 9	1		ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7 link	c.1219G>A	p.Val407Ile	missense_variant	Exon 8 of 8	1		ENSP00000335178.7	Q8NER5-3
ACVR1C	ENST00000348328.9 link	c.988G>A	p.Val330Ile	missense_variant	Exon 7 of 7	1		ENSP00000335139.6	Q8NER5-2

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000839

AC:

187

AN:

222896

Hom.:

AF XY:

0.000736

AC XY:

AN XY:

120956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0104

Gnomad SAS exome

AF:

0.000797

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000953

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

382

AN:

1431110

Hom.:

Cov.:

AF XY:

0.000280

AC XY:

199

AN XY:

711652

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00735

Gnomad4 SAS exome

AF:

0.000721

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000818

Gnomad4 OTH exome

AF:

0.000525

GnomAD4 genome

AF:

0.000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0101

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000775

Hom.:

Bravo

AF:

0.000548

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACVR1C-related disorder

Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.72

T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.74

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.024

B;.;B;B

Vest4

0.11

MVP

0.84

MPC

0.35

ClinPred

0.025

GERP RS

3.7

Varity_R

0.10

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over