rs794727365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_025074.7(FRAS1):c.2722+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,424,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FRAS1
NM_025074.7 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.57

Publications

3 publications found

Variant links:

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

FRAS1 Gene-Disease associations (from GenCC):

Fraser syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Fraser syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FRAS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012210316 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant 4-78364055-G-A is Pathogenic according to our data. Variant chr4-78364055-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.2722+1G>A		splice_donor_variant, intron_variant	Intron 22 of 73	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2 link	c.2722+1G>A		splice_donor_variant, intron_variant	Intron 22 of 41		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
FRAS1	ENST00000512123.4 link	c.2722+1G>A	splice_donor_variant, intron_variant	Intron 22 of 73	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000325942.11 link	c.2722+1G>A	splice_donor_variant, intron_variant	Intron 22 of 41	1		ENSP00000326330.6
FRAS1	ENST00000682513.1 link	c.2722+1G>A	splice_donor_variant, intron_variant	Intron 22 of 63			ENSP00000508201.1
FRAS1	ENST00000684159.1 link	c.2722+1G>A	splice_donor_variant, intron_variant	Intron 22 of 44			ENSP00000506875.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000531

AC:

AN:

188456

AF XY:

0.00000996

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000126

AC:

AN:

1424880

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

705110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32764

American (AMR)

AF:

0.00

AC:

AN:

38610

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25476

East Asian (EAS)

AF:

0.00

AC:

AN:

38080

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81244

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

1092588

Other (OTH)

AF:

0.0000338

AC:

AN:

59126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

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

Cov.:

Alfa

AF:

0.00000505

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 16, 2014

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 22 of the FRAS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FRAS1 are known to be pathogenic (PMID: 12766769, 18671281). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of FRAS1 related conditions and/or clinical features of FRAS1-related conditions (PMID: 24551978). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195697). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Fraser syndrome 1

Pathogenic:2

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2018

Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant in homozygous state or compound heterozygous state induced Fraser syndrome phenotype -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

PhyloP100

8.6

GERP RS

5.6

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.80

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over