rs7594480

Positions:

• chr2-157533956-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145259.3(ACVR1C):​c.1444A>G​(p.Ile482Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0774 in 1,591,998 control chromosomes in the GnomAD database, including 8,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (3298 hom., cov: 31)
  • Exomes 𝑓: 0.069 (5579 hom.)
• Consequence: ACVR1C NM_145259.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019722283).
• BP6: Variant 2-157533956-T-C is Benign according to our data. Variant chr2-157533956-T-C is described in ClinVar as [Benign]. Clinvar id is 1282954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR1C	NM_145259.3	c.1444A>G	p.Ile482Val	missense_variant	9/9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2	c.1294A>G	p.Ile432Val	missense_variant	9/9		NP_001104501.1
ACVR1C	NM_001111032.2	c.1204A>G	p.Ile402Val	missense_variant	8/8		NP_001104502.1
ACVR1C	NM_001111033.2	c.973A>G	p.Ile325Val	missense_variant	7/7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13	c.1444A>G	p.Ile482Val	missense_variant	9/9	1	NM_145259.3	ENSP00000243349	P1
ACVR1C	ENST00000409680.7	c.1294A>G	p.Ile432Val	missense_variant	9/9	1		ENSP00000387168
ACVR1C	ENST00000335450.7	c.1204A>G	p.Ile402Val	missense_variant	8/8	1		ENSP00000335178
ACVR1C	ENST00000348328.9	c.973A>G	p.Ile325Val	missense_variant	7/7	1		ENSP00000335139

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23456 AN: 151950 Hom.: 3294 Cov.: 31

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.0829 AC: 19211 AN: 231782 Hom.: 1684 AF XY: 0.0729 AC XY: 9156 AN XY: 125644

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00159

Gnomad SAS exome AF: 0.0186

Gnomad FIN exome AF: 0.0711

Gnomad NFE exome AF: 0.0629

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0693 AC: 99775 AN: 1439930 Hom.: 5579 Cov.: 31 AF XY: 0.0664 AC XY: 47532 AN XY: 716244

Gnomad4 AFR exome AF: 0.385

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.0219

Gnomad4 EAS exome AF: 0.00340

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0719

Gnomad4 NFE exome AF: 0.0646

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome AF: 0.154 AC: 23488 AN: 152068 Hom.: 3298 Cov.: 31 AF XY: 0.150 AC XY: 11175 AN XY: 74358

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.0645

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0801 Hom.: 1549

Bravo AF: 0.170

TwinsUK AF: 0.0661 AC: 245

ALSPAC AF: 0.0628 AC: 242

ESP6500AA AF: 0.376 AC: 1658

ESP6500EA AF: 0.0653 AC: 562

ExAC AF: 0.0876 AC: 10631

Asia WGS AF: 0.0330 AC: 118 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-0.025
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	0.0015	P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.86	N;N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.044	D;D;T;T
Polyphen		0.017	B;.;B;B
Vest4		0.087
MPC		0.32
ClinPred		0.015	T
GERP RS		5.5
Varity_R		0.39
gMVP		0.34

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

Other links and lift over

dbSNP: rs7594480; hg19: chr2-158390468; COSMIC: COSV54645344;