Genetic Variant NM_145259.3:c.970A>C (chr2-157542836-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_145259.3(ACVR1C):c.970A>C(p.Ile324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ACVR1C
NM_145259.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.34

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29224175).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1C	NM_145259.3 link	c.970A>C	p.Ile324Leu	missense_variant	Exon 6 of 9	ENST00000243349.13	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2 link	c.820A>C	p.Ile274Leu	missense_variant	Exon 6 of 9		NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2 link	c.730A>C	p.Ile244Leu	missense_variant	Exon 5 of 8		NP_001104502.1	Q8NER5-3
ACVR1C	NM_001111033.2 link	c.499A>C	p.Ile167Leu	missense_variant	Exon 4 of 7		NP_001104503.1	Q8NER5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR1C	ENST00000243349.13 link	c.970A>C	p.Ile324Leu	missense_variant	Exon 6 of 9	1	NM_145259.3	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7 link	c.820A>C	p.Ile274Leu	missense_variant	Exon 6 of 9	1		ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7 link	c.730A>C	p.Ile244Leu	missense_variant	Exon 5 of 8	1		ENSP00000335178.7	Q8NER5-3
ACVR1C	ENST00000348328.9 link	c.499A>C	p.Ile167Leu	missense_variant	Exon 4 of 7	1		ENSP00000335139.6	Q8NER5-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251258

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135806

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727182

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.0084

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.10

N;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.32

MutPred

0.60

Gain of catalytic residue at I324 (P = 0.0275);.;.;.;

MVP

0.87

MPC

0.37

ClinPred

0.49

GERP RS

4.6

Varity_R

0.12

gMVP

0.48

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over