rs4556933

Variant names:

• chr2-157587377-G-A
• rs4556933
• NM_145259.3:c.114C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_145259.3(ACVR1C):​c.114C>T​(p.Phe38Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,612,616 control chromosomes in the GnomAD database, including 131,012 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (17413 hom., cov: 31)
  • Exomes 𝑓: 0.39 (113599 hom.)
• Consequence: ACVR1C NM_145259.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 20 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

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.114C>T	p.Phe38Phe	synonymous	Exon 2 of 9	NP_660302.2	Q8NER5-1
	ACVR1C	NM_001111032.2		c.114C>T	p.Phe38Phe	synonymous	Exon 2 of 8	NP_001104502.1	Q8NER5-3
	ACVR1C	NM_001111033.2		c.114C>T	p.Phe38Phe	synonymous	Exon 2 of 7	NP_001104503.1	Q8NER5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1C	ENST00000243349.13	TSL:1 MANE Select	c.114C>T	p.Phe38Phe	synonymous	Exon 2 of 9	ENSP00000243349.7	Q8NER5-1
	ACVR1C	ENST00000335450.7	TSL:1	c.114C>T	p.Phe38Phe	synonymous	Exon 2 of 8	ENSP00000335178.7	Q8NER5-3
	ACVR1C	ENST00000348328.9	TSL:1	c.114C>T	p.Phe38Phe	synonymous	Exon 2 of 7	ENSP00000335139.6	Q8NER5-2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69646 AN: 151642 Hom.: 17380 Cov.: 31

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.386 AC: 97068 AN: 251276 AF XY: 0.375

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.395

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.389 AC: 568494 AN: 1460858 Hom.: 113599 Cov.: 44 AF XY: 0.385 AC XY: 279504 AN XY: 726778

African (AFR) AF: 0.665 AC: 22253 AN: 33442

American (AMR) AF: 0.423 AC: 18919 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 10701 AN: 26110

East Asian (EAS) AF: 0.278 AC: 11039 AN: 39682

South Asian (SAS) AF: 0.273 AC: 23558 AN: 86236

European-Finnish (FIN) AF: 0.300 AC: 16021 AN: 53404

Middle Eastern (MID) AF: 0.415 AC: 2395 AN: 5768

European-Non Finnish (NFE) AF: 0.395 AC: 439366 AN: 1111144

Other (OTH) AF: 0.402 AC: 24242 AN: 60358

GnomAD4 genome AF: 0.460 AC: 69733 AN: 151758 Hom.: 17413 Cov.: 31 AF XY: 0.450 AC XY: 33350 AN XY: 74150

African (AFR) AF: 0.660 AC: 27301 AN: 41390

American (AMR) AF: 0.440 AC: 6698 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1367 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1628 AN: 5168

South Asian (SAS) AF: 0.286 AC: 1375 AN: 4816

European-Finnish (FIN) AF: 0.290 AC: 3047 AN: 10524

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27015 AN: 67856

Other (OTH) AF: 0.455 AC: 960 AN: 2112

Alfa AF: 0.420 Hom.: 52660

Bravo AF: 0.483

Asia WGS AF: 0.334 AC: 1167 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.400

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.7
DANN	Benign	0.68
PhyloP100		1.0
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs4556933; hg19: chr2-158443889; COSMIC: COSV54644322;