Genetic Variant FRAS1:c.2423-3974T>C (chr4-78359539-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_025074.7(FRAS1):c.2423-3974T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,772 control chromosomes in the GnomAD database, including 32,134 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.64 ( 32134 hom., cov: 30)

Consequence

FRAS1
NM_025074.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00900

Publications

18 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.2423-3974T>C		intron_variant	Intron 20 of 73	ENST00000512123.4	NP_079350.5	Q86XX4-2
FRAS1	NM_001166133.2 link	c.2423-3974T>C		intron_variant	Intron 20 of 41		NP_001159605.1	Q86XX4-5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FRAS1	ENST00000512123.4 link	c.2423-3974T>C	intron_variant	Intron 20 of 73	5	NM_025074.7	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000325942.11 link	c.2423-3974T>C	intron_variant	Intron 20 of 41	1		ENSP00000326330.6	Q86XX4-5
FRAS1	ENST00000682513.1 link	c.2423-3974T>C	intron_variant	Intron 20 of 63			ENSP00000508201.1	A0A804HL50
FRAS1	ENST00000684159.1 link	c.2423-3974T>C	intron_variant	Intron 20 of 44			ENSP00000506875.1	A0A804HI32

Frequencies

GnomAD3 genomes

AF:

0.645

AC:

97751

AN:

151652

Hom.:

32107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.630

Gnomad ASJ

AF:

0.576

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.673

Gnomad OTH

AF:

0.629

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.645

AC:

97845

AN:

151772

Hom.:

32134

Cov.:

AF XY:

0.639

AC XY:

47379

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.670

AC:

27725

AN:

41362

American (AMR)

AF:

0.630

AC:

9607

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

1993

AN:

3462

East Asian (EAS)

AF:

0.261

AC:

1341

AN:

5140

South Asian (SAS)

AF:

0.428

AC:

2059

AN:

4808

European-Finnish (FIN)

AF:

0.704

AC:

7397

AN:

10510

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.673

AC:

45705

AN:

67938

Other (OTH)

AF:

0.629

AC:

1325

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1689

3378

5066

6755

8444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<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:

0.647

Hom.:

76149

Bravo

AF:

0.644

Asia WGS

AF:

0.371

AC:

1293

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.7

(source)

DANN

Benign

0.64

PhyloP100

-0.0090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over