Genetic Variant ACVR1C:p.Cys491Ser (chr2-157533929-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_145259.3(ACVR1C):c.1471T>A(p.Cys491Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,426,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.333

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.086441785).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145259.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACVR1C	NM_145259.3	MANE Select	c.1471T>A	p.Cys491Ser	missense	Exon 9 of 9	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2		c.1321T>A	p.Cys441Ser	missense	Exon 9 of 9	NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2		c.1231T>A	p.Cys411Ser	missense	Exon 8 of 8	NP_001104502.1	Q8NER5-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACVR1C	ENST00000243349.13	TSL:1 MANE Select	c.1471T>A	p.Cys491Ser	missense	Exon 9 of 9	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7	TSL:1	c.1321T>A	p.Cys441Ser	missense	Exon 9 of 9	ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7	TSL:1	c.1231T>A	p.Cys411Ser	missense	Exon 8 of 8	ENSP00000335178.7	Q8NER5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000701

AC:

AN:

1426308

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30608

American (AMR)

AF:

0.00

AC:

AN:

35376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24730

East Asian (EAS)

AF:

0.00

AC:

AN:

38712

South Asian (SAS)

AF:

0.00

AC:

AN:

79746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00000909

AC:

AN:

1099880

Other (OTH)

AF:

0.00

AC:

AN:

58804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.10

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

M_CAP

Benign

0.022

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.43

MutationAssessor

Benign

-0.69

PhyloP100

0.33

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.29

Sift

Benign

0.066

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.043

MutPred

0.41

Gain of disorder (P = 0.0132)

MVP

0.85

MPC

0.46

ClinPred

0.24

GERP RS

4.3

Varity_R

0.22

gMVP

0.58

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over