Variant 2-157534017-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145259.3(ACVR1C):c.1383G>A(p.Met461Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACVR1C	NM_145259.3 linkuse as main transcript	c.1383G>A	p.Met461Ile	missense_variant	9/9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2 linkuse as main transcript	c.1233G>A	p.Met411Ile	missense_variant	9/9		NP_001104501.1
ACVR1C	NM_001111032.2 linkuse as main transcript	c.1143G>A	p.Met381Ile	missense_variant	8/8		NP_001104502.1
ACVR1C	NM_001111033.2 linkuse as main transcript	c.912G>A	p.Met304Ile	missense_variant	7/7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13 linkuse as main transcript	c.1383G>A	p.Met461Ile	missense_variant	9/9	1	NM_145259.3	ENSP00000243349	P1	Q8NER5-1
ACVR1C	ENST00000409680.7 linkuse as main transcript	c.1233G>A	p.Met411Ile	missense_variant	9/9	1		ENSP00000387168		Q8NER5-4
ACVR1C	ENST00000335450.7 linkuse as main transcript	c.1143G>A	p.Met381Ile	missense_variant	8/8	1		ENSP00000335178		Q8NER5-3
ACVR1C	ENST00000348328.9 linkuse as main transcript	c.912G>A	p.Met304Ile	missense_variant	7/7	1		ENSP00000335139		Q8NER5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000225

AC:

AN:

222256

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

120708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000320

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428052

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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

Jan 22, 2024

The c.1383G>A (p.M461I) alteration is located in exon 9 (coding exon 9) of the ACVR1C gene. This alteration results from a G to A substitution at nucleotide position 1383, causing the methionine (M) at amino acid position 461 to be replaced by an isoleucine (I). 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

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.43

N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.025

D;D;D;D

Sift4G

Uncertain

0.049

D;T;T;T

Polyphen

0.81

P;.;P;P

Vest4

0.78

MutPred

0.65

Loss of MoRF binding (P = 0.1785);.;.;.;

MVP

0.85

MPC

1.2

ClinPred

0.79

GERP RS

5.5

Varity_R

0.73

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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