rs345513

Positions:

• chr4-78318909-A-G
• chr4-78318909-A-T

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.2060A>G​(p.Asp687Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,613,426 control chromosomes in the GnomAD database, including 129,031 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. D687D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (13884 hom., cov: 32)
  • Exomes 𝑓: 0.40 (115147 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.606

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=2.3511052E-4).
• BP6: Variant 4-78318909-A-G is Benign according to our data. Variant chr4-78318909-A-G is described in ClinVar as [Benign]. Clinvar id is 261804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78318909-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.2060A>G	p.Asp687Gly	missense_variant	18/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.2060A>G	p.Asp687Gly	missense_variant	18/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.2060A>G	p.Asp687Gly	missense_variant	18/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64602 AN: 151914 Hom.: 13869 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.412

GnomAD3 exomes AF: 0.412 AC: 102728 AN: 249100 Hom.: 21236 AF XY: 0.406 AC XY: 54905 AN XY: 135124

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.424

Gnomad SAS exome AF: 0.372

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.394

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.395 AC: 577837 AN: 1461394 Hom.: 115147 Cov.: 41 AF XY: 0.395 AC XY: 286863 AN XY: 726976

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.436

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.393

GnomAD4 genome AF: 0.425 AC: 64663 AN: 152032 Hom.: 13884 Cov.: 32 AF XY: 0.425 AC XY: 31598 AN XY: 74318

Gnomad4 AFR AF: 0.480

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.414

Alfa AF: 0.396 Hom.: 28044

Bravo AF: 0.431

TwinsUK AF: 0.391 AC: 1451

ALSPAC AF: 0.390 AC: 1503

ESP6500AA AF: 0.471 AC: 1864

ESP6500EA AF: 0.383 AC: 3188

ExAC AF: 0.410 AC: 49525

Asia WGS AF: 0.390 AC: 1355 AN: 3478

EpiCase AF: 0.382

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.6
DANN	Benign	0.068
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.00024	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.3	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.3	N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;.
Sift4G	Benign	0.53	T;T
Vest4		0.023
ClinPred		0.0015	T
GERP RS		4.0
gMVP		0.31

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: rs345513; hg19: chr4-79240063; COSMIC: COSV53590022;