rs2867014

Positions:

• chr4-78265017-G-A

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.604-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.985 in 1,562,592 control chromosomes in the GnomAD database, including 759,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67717 hom., cov: 31)
  • Exomes 𝑓: 0.99 (691647 hom.)
• Consequence: FRAS1 NM_025074.7 splice_region, intron
• Scores: Splicing: ADA: 0.0007514
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0850

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-78265017-G-A is Benign according to our data. Variant chr4-78265017-G-A is described in ClinVar as [Benign]. Clinvar id is 261808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78265017-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.604-8G>A		splice_region_variant, intron_variant		ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.604-8G>A		splice_region_variant, intron_variant			NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.604-8G>A		splice_region_variant, intron_variant		5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.940 AC: 142943 AN: 152114 Hom.: 67676 Cov.: 31

Gnomad AFR AF: 0.804

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.987

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.950

GnomAD3 exomes AF: 0.977 AC: 241753 AN: 247408 Hom.: 118386 AF XY: 0.981 AC XY: 131520 AN XY: 134130

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 0.949

Gnomad SAS exome AF: 0.986

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.990 AC: 1395975 AN: 1410360 Hom.: 691647 Cov.: 23 AF XY: 0.990 AC XY: 697982 AN XY: 704850

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.980

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.985

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.998

Gnomad4 OTH exome AF: 0.978

GnomAD4 genome AF: 0.940 AC: 143040 AN: 152232 Hom.: 67717 Cov.: 31 AF XY: 0.941 AC XY: 70064 AN XY: 74446

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.974

Gnomad4 ASJ AF: 0.982

Gnomad4 EAS AF: 0.958

Gnomad4 SAS AF: 0.987

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.997

Gnomad4 OTH AF: 0.950

Alfa AF: 0.972 Hom.: 42657

Bravo AF: 0.931

Asia WGS AF: 0.961 AC: 3342 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	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	- -
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_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00075
dbscSNV1_RF	Benign	0.068
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: rs2867014; hg19: chr4-79186171; COSMIC: COSV53613407;