Genetic Variant NM_145259.3:c.1356+6G>C (chr2-157538567-C-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_145259.3(ACVR1C):c.1356+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,547,518 control chromosomes in the GnomAD database, including 593,757 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56088 hom., cov: 31)

Exomes 𝑓: 0.88 ( 537669 hom. )

Consequence

ACVR1C
NM_145259.3 splice_region, intron

Scores

Splicing: ADA: 0.005482

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0780

Variant links:

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]

ACVR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 2-157538567-C-G is Benign according to our data. Variant chr2-157538567-C-G is described in ClinVar as [Benign]. Clinvar id is 1263226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ACVR1C	NM_145259.3 link	c.1356+6G>C	splice_region_variant, intron_variant	Intron 8 of 8	ENST00000243349.13	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2 link	c.1206+6G>C	splice_region_variant, intron_variant	Intron 8 of 8		NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2 link	c.1116+6G>C	splice_region_variant, intron_variant	Intron 7 of 7		NP_001104502.1	Q8NER5-3
ACVR1C	NM_001111033.2 link	c.885+6G>C	splice_region_variant, intron_variant	Intron 6 of 6		NP_001104503.1	Q8NER5-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACVR1C	ENST00000243349.13 link	c.1356+6G>C	splice_region_variant, intron_variant	Intron 8 of 8	1	NM_145259.3	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7 link	c.1206+6G>C	splice_region_variant, intron_variant	Intron 8 of 8	1		ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7 link	c.1116+6G>C	splice_region_variant, intron_variant	Intron 7 of 7	1		ENSP00000335178.7	Q8NER5-3
ACVR1C	ENST00000348328.9 link	c.885+6G>C	splice_region_variant, intron_variant	Intron 6 of 6	1		ENSP00000335139.6	Q8NER5-2

Frequencies

GnomAD3 genomes

AF:

0.857

AC:

130292

AN:

152046

Hom.:

56062

Cov.:

show subpopulations

Gnomad AFR

AF:

0.792

Gnomad AMI

AF:

0.907

Gnomad AMR

AF:

0.904

Gnomad ASJ

AF:

0.813

Gnomad EAS

AF:

0.925

Gnomad SAS

AF:

0.777

Gnomad FIN

AF:

0.900

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.881

Gnomad OTH

AF:

0.862

GnomAD3 exomes

AF:

0.871

AC:

183037

AN:

210122

Hom.:

80096

AF XY:

0.867

AC XY:

99155

AN XY:

114310

show subpopulations

Gnomad AFR exome

AF:

0.792

Gnomad AMR exome

AF:

0.933

Gnomad ASJ exome

AF:

0.828

Gnomad EAS exome

AF:

0.917

Gnomad SAS exome

AF:

0.772

Gnomad FIN exome

AF:

0.902

Gnomad NFE exome

AF:

0.880

Gnomad OTH exome

AF:

0.871

GnomAD4 exome

AF:

0.877

AC:

1223735

AN:

1395354

Hom.:

537669

Cov.:

AF XY:

0.874

AC XY:

605271

AN XY:

692150

show subpopulations

Gnomad4 AFR exome

AF:

0.784

Gnomad4 AMR exome

AF:

0.929

Gnomad4 ASJ exome

AF:

0.822

Gnomad4 EAS exome

AF:

0.934

Gnomad4 SAS exome

AF:

0.772

Gnomad4 FIN exome

AF:

0.902

Gnomad4 NFE exome

AF:

0.884

Gnomad4 OTH exome

AF:

0.868

GnomAD4 genome

AF:

0.857

AC:

130365

AN:

152164

Hom.:

56088

Cov.:

AF XY:

0.858

AC XY:

63846

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.791

Gnomad4 AMR

AF:

0.904

Gnomad4 ASJ

AF:

0.813

Gnomad4 EAS

AF:

0.925

Gnomad4 SAS

AF:

0.777

Gnomad4 FIN

AF:

0.900

Gnomad4 NFE

AF:

0.881

Gnomad4 OTH

AF:

0.864

Alfa

AF:

0.868

Hom.:

18566

Bravo

AF:

0.858

Asia WGS

AF:

0.868

AC:

3018

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0055

dbscSNV1_RF

Benign

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over