rs7677541

chr4-78499710-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):c.9116-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,608,900 control chromosomes in the GnomAD database, including 183,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21242 hom., cov: 33)
  • Exomes 𝑓: 0.46 (162683 hom.)
• Consequence: FRAS1 NM_025074.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005685
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.303

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-78499710-T-C is Benign according to our data. Variant chr4-78499710-T-C is described in ClinVar as [Benign]. Clinvar id is 261817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78499710-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.9116-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.9116-11T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.9116-11T>C		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78680 AN: 151750 Hom.: 21225 Cov.: 33

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.533

GnomAD3 exomes AF: 0.505 AC: 125142 AN: 248046 Hom.: 33126 AF XY: 0.512 AC XY: 68826 AN XY: 134538

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.714

Gnomad SAS exome AF: 0.662

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.464 AC: 676052 AN: 1457034 Hom.: 162683 Cov.: 31 AF XY: 0.470 AC XY: 340521 AN XY: 724824

Gnomad4 AFR exome AF: 0.658

Gnomad4 AMR exome AF: 0.450

Gnomad4 ASJ exome AF: 0.596

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.507

GnomAD4 genome AF: 0.519 AC: 78745 AN: 151866 Hom.: 21242 Cov.: 33 AF XY: 0.522 AC XY: 38747 AN XY: 74220

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.532

Alfa AF: 0.487 Hom.: 3483

Bravo AF: 0.524

Asia WGS AF: 0.670 AC: 2330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.4
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.036
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

Other links and lift over

dbSNP: rs7677541; hg19: chr4-79420864;