chr2-157533956-T-C

Variant names:

• chr2-157533956-T-C
• rs7594480
• NM_145259.3:c.1444A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 29 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 -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 VariationId 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.

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.1444A>G	p.Ile482Val	missense	Exon 9 of 9	NP_660302.2	Q8NER5-1
	ACVR1C	NM_001111031.2		c.1294A>G	p.Ile432Val	missense	Exon 9 of 9	NP_001104501.1	Q8NER5-4
	ACVR1C	NM_001111032.2		c.1204A>G	p.Ile402Val	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.1444A>G	p.Ile482Val	missense	Exon 9 of 9	ENSP00000243349.7	Q8NER5-1
	ACVR1C	ENST00000409680.7	TSL:1	c.1294A>G	p.Ile432Val	missense	Exon 9 of 9	ENSP00000387168.3	Q8NER5-4
	ACVR1C	ENST00000335450.7	TSL:1	c.1204A>G	p.Ile402Val	missense	Exon 8 of 8	ENSP00000335178.7	Q8NER5-3

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

GnomAD2 exomes AF: 0.0829 AC: 19211 AN: 231782 AF XY: 0.0729

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 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

African (AFR) AF: 0.385 AC: 12152 AN: 31586

American (AMR) AF: 0.141 AC: 5676 AN: 40252

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 561 AN: 25592

East Asian (EAS) AF: 0.00340 AC: 132 AN: 38792

South Asian (SAS) AF: 0.0193 AC: 1590 AN: 82258

European-Finnish (FIN) AF: 0.0719 AC: 3811 AN: 53020

Middle Eastern (MID) AF: 0.0511 AC: 291 AN: 5690

European-Non Finnish (NFE) AF: 0.0646 AC: 71321 AN: 1103344

Other (OTH) AF: 0.0714 AC: 4241 AN: 59396

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

African (AFR) AF: 0.375 AC: 15518 AN: 41422

American (AMR) AF: 0.145 AC: 2215 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5178

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4830

European-Finnish (FIN) AF: 0.0706 AC: 748 AN: 10590

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0645 AC: 4388 AN: 68006

Other (OTH) AF: 0.121 AC: 255 AN: 2110

Alfa AF: 0.0958 Hom.: 3153

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.044	D
Polyphen		0.017	B
Vest4		0.087
MPC		0.32
ClinPred		0.015	T
GERP RS		5.5
Varity_R		0.39
gMVP		0.34
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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