chr2-157534017-C-T

Variant names:

• chr2-157534017-C-T
• rs773114626
• NM_145259.3:c.1383G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

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]

ACMG classification

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, 0.769

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1C	NM_145259.3	MANE Select	c.1383G>A	p.Met461Ile	missense	Exon 9 of 9	NP_660302.2	Q8NER5-1
	ACVR1C	NM_001111031.2		c.1233G>A	p.Met411Ile	missense	Exon 9 of 9	NP_001104501.1	Q8NER5-4
	ACVR1C	NM_001111032.2		c.1143G>A	p.Met381Ile	missense	Exon 8 of 8	NP_001104502.1	Q8NER5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1C	ENST00000243349.13	TSL:1 MANE Select	c.1383G>A	p.Met461Ile	missense	Exon 9 of 9	ENSP00000243349.7	Q8NER5-1
	ACVR1C	ENST00000409680.7	TSL:1	c.1233G>A	p.Met411Ile	missense	Exon 9 of 9	ENSP00000387168.3	Q8NER5-4
	ACVR1C	ENST00000335450.7	TSL:1	c.1143G>A	p.Met381Ile	missense	Exon 8 of 8	ENSP00000335178.7	Q8NER5-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000225 AC: 5 AN: 222256 AF XY: 0.0000249

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428052 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710144

African (AFR) AF: 0.00 AC: 0 AN: 31032

American (AMR) AF: 0.00 AC: 0 AN: 37786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38360

South Asian (SAS) AF: 0.00 AC: 0 AN: 79994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098418

Other (OTH) AF: 0.00 AC: 0 AN: 58872

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.43	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.049	D
Polyphen		0.81	P
Vest4		0.78
MutPred		0.65		Loss of MoRF binding (P = 0.1785)
MVP		0.85
MPC		1.2
ClinPred		0.79	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.78
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs773114626; hg19: chr2-158390529;