Genetic Variant NM_025074.7:c.11056C>T (chr4-78534579-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_025074.7(FRAS1):c.11056C>T(p.Leu3686Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,607,578 control chromosomes in the GnomAD database, including 173,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15019 hom., cov: 33)

Exomes 𝑓: 0.46 ( 158535 hom. )

Consequence

FRAS1
NM_025074.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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=-0.62).

BP6

Variant 4-78534579-C-T is Benign according to our data. Variant chr4-78534579-C-T is described in ClinVar as [Benign]. Clinvar id is 261802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78534579-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.11056C>T	p.Leu3686Leu	synonymous_variant	Exon 71 of 74	ENST00000512123.4	NP_079350.5	Q86XX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 link	c.11056C>T	p.Leu3686Leu	synonymous_variant	Exon 71 of 74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65967

AN:

151988

Hom.:

15023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.574

Gnomad EAS

AF:

0.794

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.443

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.429

Gnomad OTH

AF:

0.466

GnomAD3 exomes

AF:

0.490

AC:

121714

AN:

248288

Hom.:

31742

AF XY:

0.500

AC XY:

67334

AN XY:

134714

show subpopulations

Gnomad AFR exome

AF:

0.338

Gnomad AMR exome

AF:

0.468

Gnomad ASJ exome

AF:

0.578

Gnomad EAS exome

AF:

0.791

Gnomad SAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.429

Gnomad OTH exome

AF:

0.492

GnomAD4 exome

AF:

0.458

AC:

666087

AN:

1455472

Hom.:

158535

Cov.:

AF XY:

0.464

AC XY:

336008

AN XY:

724348

show subpopulations

Gnomad4 AFR exome

AF:

0.348

Gnomad4 AMR exome

AF:

0.469

Gnomad4 ASJ exome

AF:

0.583

Gnomad4 EAS exome

AF:

0.782

Gnomad4 SAS exome

AF:

0.645

Gnomad4 FIN exome

AF:

0.435

Gnomad4 NFE exome

AF:

0.430

Gnomad4 OTH exome

AF:

0.487

GnomAD4 genome

AF:

0.434

AC:

65987

AN:

152106

Hom.:

15019

Cov.:

AF XY:

0.441

AC XY:

32756

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.345

Gnomad4 AMR

AF:

0.465

Gnomad4 ASJ

AF:

0.574

Gnomad4 EAS

AF:

0.794

Gnomad4 SAS

AF:

0.649

Gnomad4 FIN

AF:

0.443

Gnomad4 NFE

AF:

0.429

Gnomad4 OTH

AF:

0.466

Alfa

AF:

0.445

Hom.:

35722

Bravo

AF:

0.431

Asia WGS

AF:

0.675

AC:

2345

AN:

3478

EpiCase

AF:

0.452

EpiControl

AF:

0.454

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.4

DANN

Benign

0.64

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