rs4556933

chr2-157587377-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_145259.3(ACVR1C):c.114C>T(p.Phe38=) 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR1C	NM_145259.3	c.114C>T	p.Phe38=	synonymous_variant	2/9	ENST00000243349.13
ACVR1C	NM_001111032.2	c.114C>T	p.Phe38=	synonymous_variant	2/8
ACVR1C	NM_001111033.2	c.114C>T	p.Phe38=	synonymous_variant	2/7
ACVR1C	NM_001111031.2	c.-37C>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1C	ENST00000243349.13	c.114C>T	p.Phe38=	synonymous_variant	2/9	1	NM_145259.3	P1
ACVR1C	ENST00000335450.7	c.114C>T	p.Phe38=	synonymous_variant	2/8	1
ACVR1C	ENST00000348328.9	c.114C>T	p.Phe38=	synonymous_variant	2/7	1
ACVR1C	ENST00000409680.7	c.-37C>T		5_prime_UTR_variant	2/9	1

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

GnomAD3 exomes AF: 0.386 AC: 97068 AN: 251276 Hom.: 19913 AF XY: 0.375 AC XY: 50994 AN XY: 135820

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 SAS exome AF: 0.270

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

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.402

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

Gnomad4 AFR AF: 0.660

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.455

Alfa AF: 0.408 Hom.: 31813

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	7.7
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs4556933; hg19: chr2-158443889; COSMIC: COSV54644322;