rs6851427

Positions:

• chr4-78464565-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong 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 (★★).

• 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

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-78464565-G-A is Benign according to our data. Variant chr4-78464565-G-A is described in ClinVar as [Benign]. Clinvar id is 261811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78464565-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.7011G>A	p.Ala2337Ala	synonymous_variant	49/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.7011G>A	p.Ala2337Ala	synonymous_variant	49/74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.7011G>A	p.Ala2337Ala	synonymous_variant	49/64			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

GnomAD3 exomes AF: 0.371 AC: 92053 AN: 248356 Hom.: 17953 AF XY: 0.366 AC XY: 49251 AN XY: 134672

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 SAS exome AF: 0.304

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

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.463

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.376

Gnomad4 OTH exome AF: 0.341

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

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.335

Alfa AF: 0.363 Hom.: 20357

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

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.27
DANN	Benign	0.71

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

Other links and lift over

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