4-78451776-C-T

Position:

chr4-78451776-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_025074.7(FRAS1):c.6468C>T(p.His2156His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,599,366 control chromosomes in the GnomAD database, including 405,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34511 hom., cov: 32)

Exomes 𝑓: 0.71 ( 370489 hom. )

Consequence

FRAS1
NM_025074.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.32

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-78451776-C-T is Benign according to our data. Variant chr4-78451776-C-T is described in ClinVar as [Benign]. Clinvar id is 197552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78451776-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.6468C>T	p.His2156His	synonymous_variant	46/74	ENST00000512123.4	NP_079350.5	Q86XX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 link	c.6468C>T	p.His2156His	synonymous_variant	46/74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2
FRAS1	ENST00000682513.1 link	c.6468C>T	p.His2156His	synonymous_variant	46/64			ENSP00000508201.1		A0A804HL50

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101346

AN:

151884

Hom.:

34500

Cov.:

show subpopulations

Gnomad AFR

AF:

0.551

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.698

Gnomad ASJ

AF:

0.669

Gnomad EAS

AF:

0.523

Gnomad SAS

AF:

0.483

Gnomad FIN

AF:

0.750

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.742

Gnomad OTH

AF:

0.671

GnomAD3 exomes

AF:

0.676

AC:

161294

AN:

238600

Hom.:

55796

AF XY:

0.668

AC XY:

86409

AN XY:

129290

show subpopulations

Gnomad AFR exome

AF:

0.541

Gnomad AMR exome

AF:

0.689

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.535

Gnomad SAS exome

AF:

0.489

Gnomad FIN exome

AF:

0.757

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.671

GnomAD4 exome

AF:

0.711

AC:

1028905

AN:

1447364

Hom.:

370489

Cov.:

AF XY:

0.704

AC XY:

506861

AN XY:

719770

show subpopulations

Gnomad4 AFR exome

AF:

0.541

Gnomad4 AMR exome

AF:

0.693

Gnomad4 ASJ exome

AF:

0.664

Gnomad4 EAS exome

AF:

0.514

Gnomad4 SAS exome

AF:

0.492

Gnomad4 FIN exome

AF:

0.766

Gnomad4 NFE exome

AF:

0.741

Gnomad4 OTH exome

AF:

0.681

GnomAD4 genome

AF:

0.667

AC:

101405

AN:

152002

Hom.:

34511

Cov.:

AF XY:

0.664

AC XY:

49301

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.551

Gnomad4 AMR

AF:

0.698

Gnomad4 ASJ

AF:

0.669

Gnomad4 EAS

AF:

0.523

Gnomad4 SAS

AF:

0.483

Gnomad4 FIN

AF:

0.750

Gnomad4 NFE

AF:

0.742

Gnomad4 OTH

AF:

0.669

Alfa

AF:

0.718

Hom.:

46464

Bravo

AF:

0.661

Asia WGS

AF:

0.539

AC:

1875

AN:

3478

EpiCase

AF:

0.718

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2015	- -
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	-	- -

Fraser syndrome 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

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_noAF

Benign

-0.85

CADD

Benign

0.059

DANN

Benign

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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