Variant 2-157542743-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_145259.3(ACVR1C):c.1063A>G(p.Ile355Val) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033285588).

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACVR1C	NM_145259.3 linkuse as main transcript	c.1063A>G	p.Ile355Val	missense_variant	6/9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2 linkuse as main transcript	c.913A>G	p.Ile305Val	missense_variant	6/9		NP_001104501.1
ACVR1C	NM_001111032.2 linkuse as main transcript	c.823A>G	p.Ile275Val	missense_variant	5/8		NP_001104502.1
ACVR1C	NM_001111033.2 linkuse as main transcript	c.592A>G	p.Ile198Val	missense_variant	4/7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13 linkuse as main transcript	c.1063A>G	p.Ile355Val	missense_variant	6/9	1	NM_145259.3	ENSP00000243349	P1	Q8NER5-1
ACVR1C	ENST00000409680.7 linkuse as main transcript	c.913A>G	p.Ile305Val	missense_variant	6/9	1		ENSP00000387168		Q8NER5-4
ACVR1C	ENST00000335450.7 linkuse as main transcript	c.823A>G	p.Ile275Val	missense_variant	5/8	1		ENSP00000335178		Q8NER5-3
ACVR1C	ENST00000348328.9 linkuse as main transcript	c.592A>G	p.Ile198Val	missense_variant	4/7	1		ENSP00000335139		Q8NER5-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000199

AC:

AN:

250998

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000753

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000650

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000125

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

The c.1063A>G (p.I355V) alteration is located in exon 6 (coding exon 6) of the ACVR1C gene. This alteration results from a A to G substitution at nucleotide position 1063, causing the isoleucine (I) at amino acid position 355 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.0058

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.033

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.27

N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.0

N;N;N;N

REVEL

Benign

0.068

Sift

Benign

0.89

T;T;T;T

Sift4G

Benign

0.69

T;T;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.20

MVP

0.74

MPC

0.31

ClinPred

0.043

GERP RS

5.8

Varity_R

0.13

gMVP

0.39

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