Genetic Variant ACVR1C:p.Gln265His (chr2-157544593-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_145259.3(ACVR1C):c.795A>C(p.Gln265His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q265Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.222

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ACVR1C	NM_145259.3 link	c.795A>C	p.Gln265His	missense_variant	Exon 5 of 9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2 link	c.645A>C	p.Gln215His	missense_variant	Exon 5 of 9		NP_001104501.1
ACVR1C	NM_001111032.2 link	c.555A>C	p.Gln185His	missense_variant	Exon 4 of 8		NP_001104502.1
ACVR1C	NM_001111033.2 link	c.324A>C	p.Gln108His	missense_variant	Exon 3 of 7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ACVR1C	ENST00000243349.13 link	c.795A>C	p.Gln265His	missense_variant	Exon 5 of 9	1	NM_145259.3	ENSP00000243349.7
ACVR1C	ENST00000409680.7 link	c.645A>C	p.Gln215His	missense_variant	Exon 5 of 9	1		ENSP00000387168.3
ACVR1C	ENST00000335450.7 link	c.555A>C	p.Gln185His	missense_variant	Exon 4 of 8	1		ENSP00000335178.7
ACVR1C	ENST00000348328.9 link	c.324A>C	p.Gln108His	missense_variant	Exon 3 of 7	1		ENSP00000335139.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

44298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111060

Other (OTH)

AF:

0.00

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.

Eigen

Benign

-0.058

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.078

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.0

M;.;.;.

PhyloP100

0.22

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.78

MutPred

0.62

Gain of disorder (P = 0.1887);.;.;.;

MVP

0.83

MPC

1.1

ClinPred

1.0

GERP RS

-3.8

Varity_R

0.66

gMVP

0.74

Mutation Taster

=30/70

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over