4-78066003-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025074.7(FRAS1):c.95A>G(p.Asp32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,597,640 control chromosomes in the GnomAD database, including 144,182 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.50 ( 20283 hom., cov: 32)

Exomes 𝑓: 0.41 ( 123899 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.81

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.4988504E-6).

BP6

Variant 4-78066003-A-G is Benign according to our data. Variant chr4-78066003-A-G is described in ClinVar as Benign. ClinVar VariationId is 261821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.95A>G	p.Asp32Gly	missense	Exon 2 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.95A>G	p.Asp32Gly	missense	Exon 2 of 42	NP_001159605.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.95A>G	p.Asp32Gly	missense	Exon 2 of 74	ENSP00000422834.2
FRAS1	ENST00000325942.11	TSL:1	c.95A>G	p.Asp32Gly	missense	Exon 2 of 42	ENSP00000326330.6
FRAS1	ENST00000508900.2	TSL:1	c.95A>G	p.Asp32Gly	missense	Exon 2 of 20	ENSP00000423809.2

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75884

AN:

151874

Hom.:

20238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.505

Gnomad ASJ

AF:

0.538

Gnomad EAS

AF:

0.503

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.493

GnomAD2 exomes

AF:

0.448

AC:

110125

AN:

246062

AF XY:

0.441

show subpopulations

Gnomad AFR exome

AF:

0.693

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.533

Gnomad EAS exome

AF:

0.495

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.446

GnomAD4 exome

AF:

0.408

AC:

589405

AN:

1445646

Hom.:

123899

Cov.:

AF XY:

0.408

AC XY:

293665

AN XY:

719728

show subpopulations

African (AFR)

AF:

0.697

AC:

23048

AN:

33060

American (AMR)

AF:

0.496

AC:

21999

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.533

AC:

13851

AN:

25982

East Asian (EAS)

AF:

0.479

AC:

18939

AN:

39560

South Asian (SAS)

AF:

0.438

AC:

37498

AN:

85588

European-Finnish (FIN)

AF:

0.403

AC:

21457

AN:

53256

Middle Eastern (MID)

AF:

0.469

AC:

2690

AN:

5736

European-Non Finnish (NFE)

AF:

0.386

AC:

423843

AN:

1098378

Other (OTH)

AF:

0.436

AC:

26080

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

14315

28630

42945

57260

71575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13284

26568

39852

53136

66420

<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:

0.500

AC:

75988

AN:

151994

Hom.:

20283

Cov.:

AF XY:

0.501

AC XY:

37248

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.690

AC:

28635

AN:

41472

American (AMR)

AF:

0.504

AC:

7699

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.538

AC:

1867

AN:

3468

East Asian (EAS)

AF:

0.503

AC:

2596

AN:

5158

South Asian (SAS)

AF:

0.467

AC:

2252

AN:

4818

European-Finnish (FIN)

AF:

0.409

AC:

4316

AN:

10562

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.398

AC:

27020

AN:

67952

Other (OTH)

AF:

0.492

AC:

1033

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1882

3765

5647

7530

9412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.436

Hom.:

59113

Bravo

AF:

0.512

TwinsUK

AF:

0.380

AC:

1409

ALSPAC

AF:

0.392

AC:

1512

ESP6500AA

AF:

0.678

AC:

2527

ESP6500EA

AF:

0.401

AC:

3285

ExAC

AF:

0.446

AC:

53901

Asia WGS

AF:

0.500

AC:

1738

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fraser syndrome 1 (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.52

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0000055

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.9

PhyloP100

2.8

PrimateAI

Benign

0.48

PROVEAN

Benign

2.2

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.93

Vest4

0.12

ClinPred

0.0099

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.86

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over