rs199607550

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032545.4(CFC1):c.61A>C(p.Asn21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N21N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 104 hom., cov: 19)

Exomes 𝑓: 0.0048 ( 109 hom. )

Consequence

CFC1
NM_032545.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.82

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029240549).

BP6

Variant 2-130598922-T-G is Benign according to our data. Variant chr2-130598922-T-G is described in ClinVar as [Benign]. Clinvar id is 136731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-130598922-T-G is described in Lovd as [Benign]. Variant chr2-130598922-T-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFC1	NM_032545.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 6	ENST00000259216.6	NP_115934.1	P0CG37
CFC1	NM_001270420.2 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 5		NP_001257349.1	P0CG37A0A087WWV2
CFC1	NM_001270421.2 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 4		NP_001257350.1	P0CG37A0A087WX98
CFC1	XM_011511486.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFC1	ENST00000259216.6 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 6	1	NM_032545.4	ENSP00000259216.5	P0CG37
CFC1	ENST00000615342.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 5	5		ENSP00000480526.1	A0A087WWV2
CFC1	ENST00000621673.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 4	2		ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5193

AN:

132174

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.00420

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0125

AC:

1535

AN:

122496

Hom.:

AF XY:

0.0106

AC XY:

692

AN XY:

64980

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000648

Gnomad FIN exome

AF:

0.0000730

Gnomad NFE exome

AF:

0.000833

Gnomad OTH exome

AF:

0.00793

GnomAD4 exome

AF:

0.00480

AC:

4645

AN:

967394

Hom.:

109

Cov.:

AF XY:

0.00409

AC XY:

1997

AN XY:

488434

show subpopulations

Gnomad4 AFR exome

AF:

0.171

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.00377

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000340

Gnomad4 FIN exome

AF:

0.000172

Gnomad4 NFE exome

AF:

0.000465

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0394

AC:

5208

AN:

132268

Hom.:

104

Cov.:

AF XY:

0.0376

AC XY:

2389

AN XY:

63478

show subpopulations

Gnomad4 AFR

AF:

0.159

Gnomad4 AMR

AF:

0.0209

Gnomad4 ASJ

AF:

0.00420

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00181

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000646

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0213

Hom.:

ExAC

AF:

0.00666

AC:

656

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.0

DANN

Benign

0.20

DEOGEN2

Benign

0.10

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00092

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.1

.;.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

1.3

.;.;N

REVEL

Benign

0.16

Sift

Benign

0.72

.;.;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.15

MPC

1.3

ClinPred

0.0061

GERP RS

0.97

Varity_R

0.036

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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