2-157737758-C-T

Variant names:

• chr2-157737758-C-T
• rs16842009
• NM_001111067.4:c.1396-93G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001111067.4(ACVR1):​c.1396-93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,515,496 control chromosomes in the GnomAD database, including 76 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 0.012 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: ACVR1 NM_001111067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861
• Publications: 2 publications found

Genes affected

ACVR1 (HGNC:171): (activin A receptor type 1) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

ACVR1 Gene-Disease associations (from GenCC):

• fibrodysplasia ossificans progressiva

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1843/152220) while in subpopulation AFR AF = 0.0419 (1741/41526). AF 95% confidence interval is 0.0403. There are 48 homozygotes in GnomAd4. There are 856 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1843 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4	c.1396-93G>A		intron_variant	Intron 10 of 10	ENST00000434821.7	NP_001104537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7	c.1396-93G>A		intron_variant	Intron 10 of 10	1	NM_001111067.4	ENSP00000405004.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1845 AN: 152102 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.00111 AC: 1515 AN: 1363276 Hom.: 28 AF XY: 0.000924 AC XY: 632 AN XY: 684046

African (AFR) AF: 0.0397 AC: 1239 AN: 31232

American (AMR) AF: 0.00175 AC: 78 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25502

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.000119 AC: 10 AN: 84086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52564

Middle Eastern (MID) AF: 0.000894 AC: 5 AN: 5590

European-Non Finnish (NFE) AF: 0.0000215 AC: 22 AN: 1023476

Other (OTH) AF: 0.00282 AC: 161 AN: 57136

GnomAD4 genome AF: 0.0121 AC: 1843 AN: 152220 Hom.: 48 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74430

African (AFR) AF: 0.0419 AC: 1741 AN: 41526

American (AMR) AF: 0.00477 AC: 73 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68004

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.00946 Hom.: 6

Bravo AF: 0.0133

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.6
DANN	Benign	0.44
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism

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: rs16842009; hg19: chr2-158594270;