rs114476591

Variant names:

• chr2-157542786-C-T
• rs114476591
• NM_145259.3:c.1020G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_145259.3(ACVR1C):​c.1020G>A​(p.Ala340Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000969 in 1,613,994 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (25 hom.)
• Consequence: ACVR1C NM_145259.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.967

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 2-157542786-C-T is Benign according to our data. Variant chr2-157542786-C-T is described in ClinVar as [Benign]. Clinvar id is 3039145.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.967 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00361 (549/152212) while in subpopulation AMR AF= 0.0348 (532/15294). AF 95% confidence interval is 0.0323. There are 18 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 549 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1C	NM_145259.3	c.1020G>A	p.Ala340Ala	synonymous_variant	Exon 6 of 9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2	c.870G>A	p.Ala290Ala	synonymous_variant	Exon 6 of 9		NP_001104501.1
ACVR1C	NM_001111032.2	c.780G>A	p.Ala260Ala	synonymous_variant	Exon 5 of 8		NP_001104502.1
ACVR1C	NM_001111033.2	c.549G>A	p.Ala183Ala	synonymous_variant	Exon 4 of 7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13	c.1020G>A	p.Ala340Ala	synonymous_variant	Exon 6 of 9	1	NM_145259.3	ENSP00000243349.7
ACVR1C	ENST00000409680.7	c.870G>A	p.Ala290Ala	synonymous_variant	Exon 6 of 9	1		ENSP00000387168.3
ACVR1C	ENST00000335450.7	c.780G>A	p.Ala260Ala	synonymous_variant	Exon 5 of 8	1		ENSP00000335178.7
ACVR1C	ENST00000348328.9	c.549G>A	p.Ala183Ala	synonymous_variant	Exon 4 of 7	1		ENSP00000335139.6

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152094 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00258 AC: 649 AN: 251384 Hom.: 15 AF XY: 0.00213 AC XY: 290 AN XY: 135858

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000694 AC: 1015 AN: 1461782 Hom.: 25 Cov.: 30 AF XY: 0.000619 AC XY: 450 AN XY: 727202

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00361 AC: 549 AN: 152212 Hom.: 18 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74420

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0348

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.00416

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ACVR1C-related disorder Benign:1

May 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	6.9
DANN	Benign	0.72

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: rs114476591; hg19: chr2-158399298;