2-157533929-A-T

Position:

• chr2-157533929-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_145259.3(ACVR1C):​c.1471T>A​(p.Cys491Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,426,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ACVR1C NM_145259.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.333

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086441785).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR1C	NM_145259.3	c.1471T>A	p.Cys491Ser	missense_variant	9/9	ENST00000243349.13	NP_660302.2
ACVR1C	NM_001111031.2	c.1321T>A	p.Cys441Ser	missense_variant	9/9		NP_001104501.1
ACVR1C	NM_001111032.2	c.1231T>A	p.Cys411Ser	missense_variant	8/8		NP_001104502.1
ACVR1C	NM_001111033.2	c.1000T>A	p.Cys334Ser	missense_variant	7/7		NP_001104503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR1C	ENST00000243349.13	c.1471T>A	p.Cys491Ser	missense_variant	9/9	1	NM_145259.3	ENSP00000243349	P1
ACVR1C	ENST00000409680.7	c.1321T>A	p.Cys441Ser	missense_variant	9/9	1		ENSP00000387168
ACVR1C	ENST00000335450.7	c.1231T>A	p.Cys411Ser	missense_variant	8/8	1		ENSP00000335178
ACVR1C	ENST00000348328.9	c.1000T>A	p.Cys334Ser	missense_variant	7/7	1		ENSP00000335139

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000701 AC: 10 AN: 1426308 Hom.: 0 Cov.: 30 AF XY: 0.00000564 AC XY: 4 AN XY: 709168

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: 0.00000909

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.1471T>A (p.C491S) alteration is located in exon 9 (coding exon 9) of the ACVR1C gene. This alteration results from a T to A substitution at nucleotide position 1471, causing the cysteine (C) at amino acid position 491 to be replaced by a serine (S). 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	0.070
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.69	N;.;.;.
MutationTaster	Benign	0.90	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.066	T;D;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.043
MutPred		0.41		Gain of disorder (P = 0.0132);.;.;.;
MVP		0.85
MPC		0.46
ClinPred		0.24	T
GERP RS		4.3
Varity_R		0.22
gMVP		0.58

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: rs1012432779; hg19: chr2-158390441;