rs6746788

chr2-157544593-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145259.3(ACVR1C):c.795A>G(p.Gln265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,611,678 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: ACVR1C NM_145259.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.222

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-157544593-T-C is Benign according to our data. Variant chr2-157544593-T-C is described in ClinVar as [Benign]. Clinvar id is 783343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2142/152278) while in subpopulation AFR AF= 0.0484 (2010/41520). AF 95% confidence interval is 0.0466. There are 56 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR1C	NM_145259.3	c.795A>G	p.Gln265=	synonymous_variant	5/9	ENST00000243349.13
ACVR1C	NM_001111031.2	c.645A>G	p.Gln215=	synonymous_variant	5/9
ACVR1C	NM_001111032.2	c.555A>G	p.Gln185=	synonymous_variant	4/8
ACVR1C	NM_001111033.2	c.324A>G	p.Gln108=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1C	ENST00000243349.13	c.795A>G	p.Gln265=	synonymous_variant	5/9	1	NM_145259.3	P1
ACVR1C	ENST00000409680.7	c.645A>G	p.Gln215=	synonymous_variant	5/9	1
ACVR1C	ENST00000335450.7	c.555A>G	p.Gln185=	synonymous_variant	4/8	1
ACVR1C	ENST00000348328.9	c.324A>G	p.Gln108=	synonymous_variant	3/7	1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2143 AN: 152160 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00433 AC: 1077 AN: 248730 Hom.: 27 AF XY: 0.00313 AC XY: 421 AN XY: 134296

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00154 AC: 2253 AN: 1459400 Hom.: 51 Cov.: 32 AF XY: 0.00137 AC XY: 994 AN XY: 725956

Gnomad4 AFR exome AF: 0.0458

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0141 AC: 2142 AN: 152278 Hom.: 56 Cov.: 32 AF XY: 0.0134 AC XY: 997 AN XY: 74472

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00805 Hom.: 7

Bravo AF: 0.0167

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

ACVR1C-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

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	-0.54
Cadd	Benign	4.1
Dann	Benign	0.57

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: rs6746788; hg19: chr2-158401105;