4-78438731-T-G

Position:

• chr4-78438731-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):​c.5366+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,566,774 control chromosomes in the GnomAD database, including 105,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8434 hom., cov: 33)
  • Exomes 𝑓: 0.37 (96757 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.643

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-78438731-T-G is Benign according to our data. Variant chr4-78438731-T-G is described in ClinVar as [Benign]. Clinvar id is 197083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78438731-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.5366+13T>G		intron_variant		ENST00000512123.4
FRAS1	NM_001166133.2	c.5366+13T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.5366+13T>G		intron_variant		5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47385 AN: 151978 Hom.: 8424 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.315

GnomAD3 exomes AF: 0.376 AC: 71380 AN: 190090 Hom.: 13924 AF XY: 0.372 AC XY: 37912 AN XY: 101898

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.313

Gnomad SAS exome AF: 0.314

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.365 AC: 517044 AN: 1414678 Hom.: 96757 Cov.: 28 AF XY: 0.365 AC XY: 255509 AN XY: 700788

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.312 AC: 47413 AN: 152096 Hom.: 8434 Cov.: 33 AF XY: 0.315 AC XY: 23388 AN XY: 74340

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.317

Alfa AF: 0.356 Hom.: 10169

Bravo AF: 0.304

Asia WGS AF: 0.291 AC: 1013 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fraser syndrome 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.7
DANN	Benign	0.49

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: rs2170899; hg19: chr4-79359885; COSMIC: COSV53590107;