rs931606

chr4-78522696-G-A

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.10696G>A(p.Val3566Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,606,372 control chromosomes in the GnomAD database, including 239,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20748 hom., cov: 31)
  • Exomes 𝑓: 0.55 (218965 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.46

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 (MetaRNN=4.3782646E-5).
• BP6: Variant 4-78522696-G-A is Benign according to our data. Variant chr4-78522696-G-A is described in ClinVar as [Benign]. Clinvar id is 261798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78522696-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.10696G>A	p.Val3566Ile	missense_variant	69/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.10696G>A	p.Val3566Ile	missense_variant	69/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79152 AN: 151816 Hom.: 20740 Cov.: 31

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.545

GnomAD3 exomes AF: 0.521 AC: 125705 AN: 241368 Hom.: 33132 AF XY: 0.530 AC XY: 69318 AN XY: 130838

Gnomad AFR exome AF: 0.507

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.484

Gnomad SAS exome AF: 0.598

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.547 AC: 794994 AN: 1454438 Hom.: 218965 Cov.: 35 AF XY: 0.548 AC XY: 396481 AN XY: 723208

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.574

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.521 AC: 79204 AN: 151934 Hom.: 20748 Cov.: 31 AF XY: 0.517 AC XY: 38363 AN XY: 74262

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.545

Alfa AF: 0.543 Hom.: 58940

Bravo AF: 0.522

TwinsUK AF: 0.559 AC: 2073

ALSPAC AF: 0.558 AC: 2151

ESP6500AA AF: 0.519 AC: 1938

ESP6500EA AF: 0.545 AC: 4480

ExAC AF: 0.519 AC: 62682

Asia WGS AF: 0.502 AC: 1745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 1 Benign:3

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. -
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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	14
Dann	Benign	0.18
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.000044	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	1.0	T
Vest4		0.026
ClinPred		0.0091	T
GERP RS		4.9
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs931606; hg19: chr4-79443850; COSMIC: COSV53595004;