4-78400853-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_025074.7(FRAS1):c.4095C>T(p.Ile1365Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,613,694 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 4 hom. )

Consequence

FRAS1
NM_025074.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.171

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 4-78400853-C-T is Benign according to our data. Variant chr4-78400853-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435257.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BP7

Synonymous conserved (PhyloP=0.171 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000834 (127/152266) while in subpopulation NFE AF= 0.00156 (106/68020). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 74	ENST00000512123.4	NP_079350.5	Q86XX4-2
FRAS1	NM_001166133.2 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 42		NP_001159605.1	Q86XX4-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FRAS1	ENST00000512123.4 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 74	5	NM_025074.7	ENSP00000422834.2	Q86XX4-2
FRAS1	ENST00000325942.11 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 42	1		ENSP00000326330.6	Q86XX4-5
FRAS1	ENST00000682513.1 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 64			ENSP00000508201.1	A0A804HL50
FRAS1	ENST00000684159.1 link	c.4095C>T	p.Ile1365Ile	synonymous_variant	Exon 30 of 45			ENSP00000506875.1	A0A804HI32

Frequencies

GnomAD3 genomes

AF:

0.000835

AC:

127

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000639

AC:

159

AN:

248754

Hom.:

AF XY:

0.000660

AC XY:

AN XY:

134932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.000984

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000541

AC:

790

AN:

1461428

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

424

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.000572

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152266

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000450

EpiCase

AF:

0.000818

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jul 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.9

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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