rs13123710

Positions:

• chr4-78464478-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.6924C>T​(p.Val2308=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,782 control chromosomes in the GnomAD database, including 5,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (325 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4705 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.79

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-78464478-C-T is Benign according to our data. Variant chr4-78464478-C-T is described in ClinVar as [Benign]. Clinvar id is 261810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78464478-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.6924C>T	p.Val2308=	synonymous_variant	49/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.6924C>T	p.Val2308=	synonymous_variant	49/74	5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.6924C>T	p.Val2308=	synonymous_variant	49/64

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8393 AN: 152126 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0575 AC: 14312 AN: 248878 Hom.: 571 AF XY: 0.0582 AC XY: 7851 AN XY: 135002

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0286

Gnomad FIN exome AF: 0.0940

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0755 AC: 110315 AN: 1461538 Hom.: 4705 Cov.: 32 AF XY: 0.0742 AC XY: 53939 AN XY: 727068

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0244

Gnomad4 ASJ exome AF: 0.0558

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0297

Gnomad4 FIN exome AF: 0.0937

Gnomad4 NFE exome AF: 0.0862

Gnomad4 OTH exome AF: 0.0636

GnomAD4 genome AF: 0.0551 AC: 8391 AN: 152244 Hom.: 325 Cov.: 32 AF XY: 0.0539 AC XY: 4009 AN XY: 74432

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0888

Gnomad4 NFE AF: 0.0837

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0707 Hom.: 590

Bravo AF: 0.0494

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0739

EpiControl AF: 0.0756

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Fraser syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs13123710; hg19: chr4-79385632; COSMIC: COSV53626018;