rs148509395

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.776T>G(p.Leu259Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00409 in 1,603,920 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 35 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.77

Publications

6 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=0.0076170564).

BP6

Variant 4-78266922-T-G is Benign according to our data. Variant chr4-78266922-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00372 (567/152368) while in subpopulation SAS AF = 0.0087 (42/4830). AF 95% confidence interval is 0.00661. There are 1 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 35 AR,AD 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.776T>G	p.Leu259Arg	missense	Exon 8 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.776T>G	p.Leu259Arg	missense	Exon 8 of 42	NP_001159605.1	Q86XX4-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.776T>G	p.Leu259Arg	missense	Exon 8 of 74	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000325942.11	TSL:1	c.776T>G	p.Leu259Arg	missense	Exon 8 of 42	ENSP00000326330.6	Q86XX4-5
FRAS1	ENST00000508900.2	TSL:1	c.776T>G	p.Leu259Arg	missense	Exon 8 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes

AF:

0.00372

AC:

567

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00454

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00508

AC:

1191

AN:

234368

AF XY:

0.00561

show subpopulations

Gnomad AFR exome

AF:

0.000625

Gnomad AMR exome

AF:

0.00170

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00963

Gnomad NFE exome

AF:

0.00406

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00413

AC:

5988

AN:

1451552

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

3218

AN XY:

721038

show subpopulations

African (AFR)

AF:

0.000540

AC:

AN:

33348

American (AMR)

AF:

0.00170

AC:

AN:

43558

Ashkenazi Jewish (ASJ)

AF:

0.00744

AC:

193

AN:

25926

East Asian (EAS)

AF:

0.000127

AC:

AN:

39492

South Asian (SAS)

AF:

0.0133

AC:

1114

AN:

84004

European-Finnish (FIN)

AF:

0.00954

AC:

505

AN:

52962

Middle Eastern (MID)

AF:

0.00782

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00341

AC:

3768

AN:

1106404

Other (OTH)

AF:

0.00443

AC:

266

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

273

547

820

1094

1367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.00372

AC:

567

AN:

152368

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41590

American (AMR)

AF:

0.00170

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00870

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0119

AC:

126

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00454

AC:

309

AN:

68038

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.00265

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000249

AC:

ESP6500EA

AF:

0.00479

AC:

ExAC

AF:

0.00516

AC:

624

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Fraser syndrome 1 (2)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.018

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.9

PhyloP100

3.8

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.020

Vest4

0.32

MVP

0.69

ClinPred

0.047

GERP RS

4.1

gMVP

0.88

Mutation Taster

=60/40

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over