4-78066003-A-G

Position:

chr4-78066003-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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=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 id is 261821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78066003-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	2/74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	2/42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.95A>G	p.Asp32Gly	missense_variant	2/74	5	NM_025074.7	ENSP00000422834	P1	Q86XX4-2

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

GnomAD3 exomes

AF:

0.448

AC:

110125

AN:

246062

Hom.:

25557

AF XY:

0.441

AC XY:

58787

AN XY:

133448

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 SAS exome

AF:

0.437

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

Gnomad4 AFR exome

AF:

0.697

Gnomad4 AMR exome

AF:

0.496

Gnomad4 ASJ exome

AF:

0.533

Gnomad4 EAS exome

AF:

0.479

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.403

Gnomad4 NFE exome

AF:

0.386

Gnomad4 OTH exome

AF:

0.436

GnomAD4 genome

AF:

0.500

AC:

75988

AN:

151994

Hom.:

20283

Cov.:

AF XY:

0.501

AC XY:

37248

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.690

Gnomad4 AMR

AF:

0.504

Gnomad4 ASJ

AF:

0.538

Gnomad4 EAS

AF:

0.503

Gnomad4 SAS

AF:

0.467

Gnomad4 FIN

AF:

0.409

Gnomad4 NFE

AF:

0.398

Gnomad4 OTH

AF:

0.492

Alfa

AF:

0.423

Hom.:

36073

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fraser syndrome 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.52

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.28

T;T

MetaRNN

Benign

0.0000055

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.9

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

2.2

N;D

REVEL

Benign

0.11

Sift

Benign

1.0

T;D

Sift4G

Benign

0.93

T;T

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

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

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