NM_025074.7:c.604-8G>A

Variant names:

• chr4-78265017-G-A
• rs2867014
• NM_025074.7:c.604-8G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Fraser syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Fraser syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.604-8G>A		splice_region_variant, intron_variant	Intron 6 of 73	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.604-8G>A		splice_region_variant, intron_variant	Intron 6 of 41		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.604-8G>A		splice_region_variant, intron_variant	Intron 6 of 73	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

GnomAD2 exomes AF: 0.977 AC: 241753 AN: 247408 AF XY: 0.981

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 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

African (AFR) AF: 0.795 AC: 25683 AN: 32312

American (AMR) AF: 0.981 AC: 43650 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 25310 AN: 25826

East Asian (EAS) AF: 0.958 AC: 37773 AN: 39434

South Asian (SAS) AF: 0.985 AC: 83469 AN: 84768

European-Finnish (FIN) AF: 1.00 AC: 53246 AN: 53248

Middle Eastern (MID) AF: 0.977 AC: 5549 AN: 5682

European-Non Finnish (NFE) AF: 0.998 AC: 1063890 AN: 1065902

Other (OTH) AF: 0.978 AC: 57405 AN: 58674

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

African (AFR) AF: 0.804 AC: 33354 AN: 41498

American (AMR) AF: 0.974 AC: 14897 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3410 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4952 AN: 5168

South Asian (SAS) AF: 0.987 AC: 4763 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10620

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67842 AN: 68036

Other (OTH) AF: 0.950 AC: 2009 AN: 2114

Alfa AF: 0.969 Hom.: 48289

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

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

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.33
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2867014; hg19: chr4-79186171; COSMIC: COSV53613407;