rs6851427

Variant names:

• chr4-78464565-G-A
• rs6851427
• NM_025074.7:c.7011G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.7011G>A​(p.Ala2337Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,104 control chromosomes in the GnomAD database, including 109,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2337A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (8800 hom., cov: 31)
  • Exomes 𝑓: 0.37 (100644 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.52
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 4-78464565-G-A is Benign according to our data. Variant chr4-78464565-G-A is described in ClinVar as Benign. ClinVar VariationId is 261811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 74	NP_079350.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 74	ENSP00000422834.2
	FRAS1	ENST00000682513.1		c.7011G>A	p.Ala2337Ala	synonymous	Exon 49 of 64	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49493 AN: 151860 Hom.: 8787 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.371 AC: 92053 AN: 248356 AF XY: 0.366

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.367 AC: 536916 AN: 1461126 Hom.: 100644 Cov.: 41 AF XY: 0.366 AC XY: 266054 AN XY: 726828

African (AFR) AF: 0.173 AC: 5774 AN: 33466

American (AMR) AF: 0.463 AC: 20708 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8630 AN: 26132

East Asian (EAS) AF: 0.306 AC: 12139 AN: 39670

South Asian (SAS) AF: 0.305 AC: 26274 AN: 86218

European-Finnish (FIN) AF: 0.443 AC: 23651 AN: 53350

Middle Eastern (MID) AF: 0.283 AC: 1630 AN: 5756

European-Non Finnish (NFE) AF: 0.376 AC: 417528 AN: 1111516

Other (OTH) AF: 0.341 AC: 20582 AN: 60336

GnomAD4 genome AF: 0.326 AC: 49534 AN: 151978 Hom.: 8800 Cov.: 31 AF XY: 0.329 AC XY: 24410 AN XY: 74258

African (AFR) AF: 0.179 AC: 7423 AN: 41442

American (AMR) AF: 0.407 AC: 6214 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1160 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1518 AN: 5146

South Asian (SAS) AF: 0.303 AC: 1460 AN: 4816

European-Finnish (FIN) AF: 0.436 AC: 4602 AN: 10560

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26031 AN: 67972

Other (OTH) AF: 0.335 AC: 709 AN: 2114

Alfa AF: 0.356 Hom.: 30593

Bravo AF: 0.320

Asia WGS AF: 0.306 AC: 1067 AN: 3476

EpiCase AF: 0.367

EpiControl AF: 0.362

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 1 Benign:3

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.27
DANN	Benign	0.71
PhyloP100		-2.5
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6851427; hg19: chr4-79385719; COSMIC: COSV53590139;