2-157533979-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_145259.3(ACVR1C):c.1421C>G(p.Thr474Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,599,348 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: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.92

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1C	NM_145259.3 link	c.1421C>G	p.Thr474Ser	missense_variant	Exon 9 of 9	ENST00000243349.13	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2 link	c.1271C>G	p.Thr424Ser	missense_variant	Exon 9 of 9		NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2 link	c.1181C>G	p.Thr394Ser	missense_variant	Exon 8 of 8		NP_001104502.1	Q8NER5-3
ACVR1C	NM_001111033.2 link	c.950C>G	p.Thr317Ser	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.1421C>G	p.Thr474Ser	missense_variant	Exon 9 of 9	1	NM_145259.3	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7 link	c.1271C>G	p.Thr424Ser	missense_variant	Exon 9 of 9	1		ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7 link	c.1181C>G	p.Thr394Ser	missense_variant	Exon 8 of 8	1		ENSP00000335178.7	Q8NER5-3
ACVR1C	ENST00000348328.9 link	c.950C>G	p.Thr317Ser	missense_variant	Exon 7 of 7	1		ENSP00000335139.6	Q8NER5-2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000417

AC:

AN:

239712

Hom.:

AF XY:

0.00000770

AC XY:

AN XY:

129878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000898

AC:

AN:

1447304

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719860

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:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1421C>G (p.T474S) alteration is located in exon 9 (coding exon 9) of the ACVR1C gene. This alteration results from a C to G substitution at nucleotide position 1421, causing the threonine (T) at amino acid position 474 to be replaced by a serine (S). 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

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;.;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.47

N;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Benign

0.082

T;T;T;T

Polyphen

0.74

P;.;B;B

Vest4

0.72

MutPred

0.76

Gain of phosphorylation at T474 (P = 0.2093);.;.;.;

MVP

0.96

MPC

0.85

ClinPred

0.94

GERP RS

5.5

Varity_R

0.42

gMVP

0.66

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