12-51951789-C-T

Variant names:

• chr12-51951789-C-T
• rs1941300785
• NM_004302.5:c.46C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004302.5(ACVR1B):​c.46C>T​(p.Leu16Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,145,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ACVR1B NM_004302.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.634

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3544161).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1B	NM_004302.5	c.46C>T	p.Leu16Phe	missense_variant	Exon 1 of 9	ENST00000257963.9	NP_004293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1B	ENST00000257963.9	c.46C>T	p.Leu16Phe	missense_variant	Exon 1 of 9	1	NM_004302.5	ENSP00000257963.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000122 AC: 14 AN: 1145944 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 6 AN XY: 547606

Gnomad4 AFR exome AF: 0.00

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: 0.0000148

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000843 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

Sep 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46C>T (p.L16F) alteration is located in exon 1 (coding exon 1) of the ACVR1B gene. This alteration results from a C to T substitution at nucleotide position 46, causing the leucine (L) at amino acid position 16 to be replaced by a phenylalanine (F). 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	0.067
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.54	T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.0	N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.77	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.087	T;T;T;D
Polyphen		0.81	P;P;P;D
Vest4		0.39
MVP		0.83
MPC		2.2
ClinPred		0.53	D
GERP RS		2.6
Varity_R		0.069
gMVP		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: rs1941300785; hg19: chr12-52345573;