rs61729366

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025074.7(FRAS1):c.9806G>A(p.Arg3269Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,603,438 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3269W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0056 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 92 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 9.79

Publications

8 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=0.016093582).

BP6

Variant 4-78511299-G-A is Benign according to our data. Variant chr4-78511299-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00564 (858/152232) while in subpopulation NFE AF = 0.00989 (673/68026). AF 95% confidence interval is 0.00927. There are 3 homozygotes in GnomAd4. There are 404 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

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.9806G>A	p.Arg3269Gln	missense	Exon 64 of 74	NP_079350.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.9806G>A	p.Arg3269Gln	missense	Exon 64 of 74	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000915768.1		c.9578G>A	p.Arg3193Gln	missense	Exon 63 of 73	ENSP00000585827.1
FRAS1	ENST00000682513.1		c.9806G>A	p.Arg3269Gln	missense	Exon 64 of 64	ENSP00000508201.1	A0A804HL50

Frequencies

GnomAD3 genomes

AF:

0.00564

AC:

858

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00989

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00518

AC:

1276

AN:

246530

AF XY:

0.00480

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00251

Gnomad ASJ exome

AF:

0.000409

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00361

Gnomad NFE exome

AF:

0.00933

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00982

AC:

14252

AN:

1451206

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

6793

AN XY:

719792

show subpopulations

African (AFR)

AF:

0.000932

AC:

AN:

33272

American (AMR)

AF:

0.00255

AC:

113

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.000541

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39402

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85750

European-Finnish (FIN)

AF:

0.00430

AC:

229

AN:

53248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.0121

AC:

13327

AN:

1103854

Other (OTH)

AF:

0.00891

AC:

534

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

700

1401

2101

2802

3502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

524

1048

1572

2096

2620

<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:

0.00564

AC:

858

AN:

152232

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

404

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

41524

American (AMR)

AF:

0.00523

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00989

AC:

673

AN:

68026

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00877

Hom.:

Bravo

AF:

0.00581

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00119

AC:

ESP6500EA

AF:

0.00981

AC:

ExAC

AF:

0.00547

AC:

663

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00998

EpiControl

AF:

0.00969

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Fraser syndrome 1 (3)

Congenital diaphragmatic hernia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.032

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

PhyloP100

9.8

PrimateAI

Uncertain

0.75

Sift4G

Pathogenic

0.0

Vest4

0.94

MVP

0.84

ClinPred

0.038

GERP RS

5.7

gMVP

0.45

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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