12-51975399-G-A

Variant names:

• chr12-51975399-G-A
• rs938359774
• NM_004302.5:c.226G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004302.5(ACVR1B):​c.226G>A​(p.Val76Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACVR1B NM_004302.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

Genes affected

ACVR1B (HGNC:172): (activin A receptor type 1B) This gene encodes an activin A type IB receptor. 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 and two type II receptors. This protein is a type I receptor which is essential for signaling. Mutations in this gene are associated with pituitary tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2606978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1B	NM_004302.5	c.226G>A	p.Val76Ile	missense_variant	Exon 2 of 9	ENST00000257963.9	NP_004293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1B	ENST00000257963.9	c.226G>A	p.Val76Ile	missense_variant	Exon 2 of 9	1	NM_004302.5	ENSP00000257963.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226G>A (p.V76I) alteration is located in exon 2 (coding exon 2) of the ACVR1B gene. This alteration results from a G to A substitution at nucleotide position 226, causing the valine (V) at amino acid position 76 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.
Eigen	Benign	-0.043
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.81	L;L;L;.;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.020	N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.57	T;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;D;T;T
Polyphen		0.0010	B;B;B;.;B;.
Vest4		0.12
MutPred		0.54		Gain of catalytic residue at A78 (P = 0);Gain of catalytic residue at A78 (P = 0);Gain of catalytic residue at A78 (P = 0);.;Gain of catalytic residue at A78 (P = 0);.;
MVP		0.75
MPC		0.85
ClinPred		0.74	D
GERP RS		4.9
Varity_R		0.061
gMVP		0.68

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: rs938359774; hg19: chr12-52369183;