chr4-78511299-G-A

Position:

chr4-78511299-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★★). Synonymous variant affecting the same amino acid position (i.e. R3269R) has been classified as Likely benign.

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:10O:1

Conservation

PhyloP100: 9.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 198348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78511299-G-A is described in Lovd as [Likely_benign]. Variant chr4-78511299-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.9806G>A	p.Arg3269Gln	missense_variant	64/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.9806G>A	p.Arg3269Gln	missense_variant	64/74	5	NM_025074.7	P1	Q86XX4-2
FRAS1	ENST00000682513.1 linkuse as main transcript	c.9806G>A	p.Arg3269Gln	missense_variant	64/64

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

GnomAD3 exomes

AF:

0.00518

AC:

1276

AN:

246530

Hom.:

AF XY:

0.00480

AC XY:

642

AN XY:

133646

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 SAS exome

AF:

0.0000663

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

Gnomad4 AFR exome

AF:

0.000932

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.000541

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00430

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00891

GnomAD4 genome

AF:

0.00564

AC:

858

AN:

152232

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

404

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00157

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00989

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00911

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

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2022	Variant summary: FRAS1 c.9806G>A (p.Arg3269Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 246530 control chromosomes (gnomAD), predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FRAS1: BS2 -

Fraser syndrome 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Congenital diaphragmatic hernia

Other:1

risk factor, no assertion criteria provided

research

Daryl Scott Lab, Baylor College of Medicine

Nov 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

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

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.75

Sift4G

Pathogenic

0.0

Vest4

0.94

MVP

0.84

ClinPred

0.038

GERP RS

5.7

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over