rs746231039

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_032545.4(CFC1):c.522delC(p.Ala175ArgfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 14)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

CFC1
NM_032545.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 0.0630

Publications

1 publications found

Variant links:

Genes affected

CFC1 (HGNC:18292): (cryptic, EGF-CFC family member 1) This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

CFC1 Gene-Disease associations (from GenCC):

heterotaxy, visceral, 2, autosomal
Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

CFC1 links:

ENSG00000296239 (HGNC:):

ENSG00000296239 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 2-130593026-CG-C is Benign according to our data. Variant chr2-130593026-CG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5188.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFC1	NM_032545.4 link	c.522delC	p.Ala175ArgfsTer56	frameshift_variant	Exon 6 of 6	ENST00000259216.6	NP_115934.1	P0CG37
CFC1	NM_001270420.2 link	c.407delC	p.Ala136GlyfsTer61	frameshift_variant	Exon 5 of 5		NP_001257349.1	P0CG37A0A087WWV2
CFC1	NM_001270421.2 link	c.297delC	p.Ala100ArgfsTer56	frameshift_variant	Exon 4 of 4		NP_001257350.1	P0CG37A0A087WX98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFC1	ENST00000259216.6 link	c.522delC	p.Ala175ArgfsTer56	frameshift_variant	Exon 6 of 6	1	NM_032545.4	ENSP00000259216.5	P0CG37
CFC1	ENST00000615342.4 link	c.407delC	p.Ala136GlyfsTer61	frameshift_variant	Exon 5 of 5	5		ENSP00000480526.1	A0A087WWV2
CFC1	ENST00000621673.4 link	c.297delC	p.Ala100ArgfsTer56	frameshift_variant	Exon 4 of 4	2		ENSP00000480843.1	A0A087WX98
ENSG00000296239	ENST00000737538.1 link	n.*183delG		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000885

AC:

AN:

106242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00123

Gnomad ASJ

AF:

0.00103

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00694

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00127

AC:

AN:

53658

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00344

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.00210

GnomAD4 exome

AF:

0.00151

AC:

669

AN:

443488

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

386

AN XY:

233326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000412

AC:

AN:

12136

American (AMR)

AF:

0.000866

AC:

AN:

18480

Ashkenazi Jewish (ASJ)

AF:

0.00397

AC:

AN:

13592

East Asian (EAS)

AF:

0.00

AC:

AN:

30650

South Asian (SAS)

AF:

0.00308

AC:

137

AN:

44536

European-Finnish (FIN)

AF:

0.0000696

AC:

AN:

28716

Middle Eastern (MID)

AF:

0.00206

AC:

AN:

1944

European-Non Finnish (NFE)

AF:

0.00146

AC:

392

AN:

267742

Other (OTH)

AF:

0.00230

AC:

AN:

25692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000884

AC:

AN:

106308

Hom.:

Cov.:

AF XY:

0.000922

AC XY:

AN XY:

48824

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000271

AC:

AN:

25876

American (AMR)

AF:

0.00123

AC:

AN:

9758

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

2904

East Asian (EAS)

AF:

0.00

AC:

AN:

3942

South Asian (SAS)

AF:

0.00231

AC:

AN:

2592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5986

Middle Eastern (MID)

AF:

0.00752

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

52958

Other (OTH)

AF:

0.00

AC:

AN:

1314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.316

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000298

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 2, autosomal

Pathogenic:1Uncertain:1

Mar 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Mar 28, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also identified in a patient with isolated double-outlet right ventricle and inherited from an asymptomatic parent in the published literature (PMID: 11799476); Observed in two unrelated patients with various laterality defects in published literature; one patient inherited the variant from an asymptomatic parent in addition to also having a variant in another heterotaxy-related gene (PMID: 11062482); Published in vitro functional studies in zebrafish support a damaging effect, as this variant was found to be absent from the cell surface and was unable to rescue MZoep mutant phenotype (PMID: 11062482); Frameshift variant predicted to result in abnormal protein length as the last 49 amino acids are replaced with 55 different amino acids; This variant is associated with the following publications: (PMID: 31589614, Maaged2022[Review], 30293987, 11799476, 11062482) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFC1: BS1, BS2 -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.063

Mutation Taster

=113/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over