rs730882180

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025074.7(FRAS1):c.7522+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,046 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FRAS1
NM_025074.7 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.63

Publications

0 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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of -1, new splice context is: cagGTtggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-78472331-G-T is Pathogenic according to our data. Variant chr4-78472331-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2816.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.7522+1G>T		splice_donor_variant, intron_variant	Intron 52 of 73	ENST00000512123.4	NP_079350.5	Q86XX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 link	c.7522+1G>T		splice_donor_variant, intron_variant	Intron 52 of 73	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2
FRAS1	ENST00000682513.1 link	c.7522+1G>T		splice_donor_variant, intron_variant	Intron 52 of 63			ENSP00000508201.1		A0A804HL50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000416

AC:

AN:

240176

AF XY:

0.00000768

show subpopulations

Gnomad AFR exome

AF:

0.0000655

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:

6.91e-7

AC:

AN:

1447046

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717996

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

33002

American (AMR)

AF:

0.00

AC:

AN:

43150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25596

East Asian (EAS)

AF:

0.00

AC:

AN:

39412

South Asian (SAS)

AF:

0.00

AC:

AN:

84422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103038

Other (OTH)

AF:

0.00

AC:

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fraser syndrome 1

Pathogenic:3

Jul 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jan 06, 2025

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 52 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 Fraser syndrome (PMID: 17163535). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2816). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (PMID: 17163535). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.6

GERP RS

5.1

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: -2

DS_DL_spliceai

0.90

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