Genetic Variant ACVR1C:c.1226-50T>C (chr2-157538753-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_145259.3(ACVR1C):c.1226-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,406,240 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 339 hom. )

Consequence

ACVR1C
NM_145259.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.310

Publications

2 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-157538753-A-G is Benign according to our data. Variant chr2-157538753-A-G is described in ClinVar as Benign. ClinVar VariationId is 1295039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145259.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACVR1C	NM_145259.3	MANE Select	c.1226-50T>C	intron	N/A	NP_660302.2	Q8NER5-1
ACVR1C	NM_001111031.2		c.1076-50T>C	intron	N/A	NP_001104501.1	Q8NER5-4
ACVR1C	NM_001111032.2		c.986-50T>C	intron	N/A	NP_001104502.1	Q8NER5-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACVR1C	ENST00000243349.13	TSL:1 MANE Select	c.1226-50T>C	intron	N/A	ENSP00000243349.7	Q8NER5-1
ACVR1C	ENST00000409680.7	TSL:1	c.1076-50T>C	intron	N/A	ENSP00000387168.3	Q8NER5-4
ACVR1C	ENST00000335450.7	TSL:1	c.986-50T>C	intron	N/A	ENSP00000335178.7	Q8NER5-3

Frequencies

GnomAD3 genomes

AF:

0.00963

AC:

1464

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.0958

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.0459

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0184

AC:

2813

AN:

153262

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.000273

Gnomad AMR exome

AF:

0.0542

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.0989

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.00643

AC:

8069

AN:

1254078

Hom.:

339

Cov.:

AF XY:

0.00622

AC XY:

3820

AN XY:

613918

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

26460

American (AMR)

AF:

0.0424

AC:

930

AN:

21948

Ashkenazi Jewish (ASJ)

AF:

0.00985

AC:

194

AN:

19692

East Asian (EAS)

AF:

0.118

AC:

3902

AN:

33132

South Asian (SAS)

AF:

0.00378

AC:

189

AN:

50038

European-Finnish (FIN)

AF:

0.0378

AC:

1758

AN:

46556

Middle Eastern (MID)

AF:

0.00118

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.000592

AC:

592

AN:

999970

Other (OTH)

AF:

0.00963

AC:

493

AN:

51218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00961

AC:

1462

AN:

152162

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

903

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41564

American (AMR)

AF:

0.0169

AC:

258

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.0958

AC:

497

AN:

5186

South Asian (SAS)

AF:

0.00828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0459

AC:

484

AN:

10548

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

67988

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00396

Hom.:

Bravo

AF:

0.00850

Asia WGS

AF:

0.0480

AC:

166

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.7

(source)

DANN

Benign

0.82

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over