4-78499857-G-T

Position:

• chr4-78499857-G-T

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.9252G>T​(p.Arg3084=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,000 control chromosomes in the GnomAD database, including 31,623 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. R3084R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1897 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29726 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.172

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=-0.58).
• BP6: Variant 4-78499857-G-T is Benign according to our data. Variant chr4-78499857-G-T is described in ClinVar as [Benign]. Clinvar id is 261820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78499857-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.172 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.9252G>T	p.Arg3084=	synonymous_variant	61/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.9252G>T	p.Arg3084=	synonymous_variant	61/74	5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.9252G>T	p.Arg3084=	synonymous_variant	61/64

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21945 AN: 152092 Hom.: 1897 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.140 AC: 34863 AN: 248832 Hom.: 3240 AF XY: 0.140 AC XY: 18917 AN XY: 134982

Gnomad AFR exome AF: 0.0775

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00167

Gnomad SAS exome AF: 0.0581

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.191 AC: 279029 AN: 1460790 Hom.: 29726 Cov.: 34 AF XY: 0.187 AC XY: 135687 AN XY: 726624

Gnomad4 AFR exome AF: 0.0783

Gnomad4 AMR exome AF: 0.0838

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.00209

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.144 AC: 21945 AN: 152210 Hom.: 1897 Cov.: 32 AF XY: 0.138 AC XY: 10305 AN XY: 74426

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.138

Alfa AF: 0.179 Hom.: 3247

Bravo AF: 0.140

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.201

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

Feb 01, 2024

- -

Fraser syndrome 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.0
DANN	Benign	0.61

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: rs11933630; hg19: chr4-79421011; COSMIC: COSV53592637;