rs78575519

chr4-78421957-G-Achr4-78421957-G-C

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.4635G>A(p.Pro1545=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,612,866 control chromosomes in the GnomAD database, including 40,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2599 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38264 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.01

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=-0.85).
• BP6: Variant 4-78421957-G-A is Benign according to our data. Variant chr4-78421957-G-A is described in ClinVar as [Benign]. Clinvar id is 261807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78421957-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.4635G>A	p.Pro1545=	synonymous_variant	34/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.4635G>A	p.Pro1545=	synonymous_variant	34/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.4635G>A	p.Pro1545=	synonymous_variant	34/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26307 AN: 151726 Hom.: 2599 Cov.: 30

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0819

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.177 AC: 43928 AN: 248534 Hom.: 4726 AF XY: 0.175 AC XY: 23533 AN XY: 134794

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.0913

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.220 AC: 320878 AN: 1461024 Hom.: 38264 Cov.: 34 AF XY: 0.215 AC XY: 156608 AN XY: 726762

Gnomad4 AFR exome AF: 0.0874

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.173 AC: 26314 AN: 151842 Hom.: 2599 Cov.: 30 AF XY: 0.169 AC XY: 12537 AN XY: 74184

Gnomad4 AFR AF: 0.0956

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0824

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.169

Alfa AF: 0.208 Hom.: 1850

Bravo AF: 0.167

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

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	-0.85
Cadd	Benign	0.24
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs78575519; hg19: chr4-79343111;