4-78507468-C-T

Position:

chr4-78507468-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_025074.7(FRAS1):c.9364C>T(p.Arg3122Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,612,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

FRAS1
NM_025074.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 1.33

Variant links:

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]

FRAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2384445).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000466 (71/152226) while in subpopulation AMR AF= 0.00229 (35/15294). AF 95% confidence interval is 0.00169. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7 linkuse as main transcript	c.9364C>T	p.Arg3122Trp	missense_variant	62/74	ENST00000512123.4	NP_079350.5	Q86XX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4 linkuse as main transcript	c.9364C>T	p.Arg3122Trp	missense_variant	62/74	5	NM_025074.7	ENSP00000422834.2		Q86XX4-2
FRAS1	ENST00000682513.1 linkuse as main transcript	c.9364C>T	p.Arg3122Trp	missense_variant	62/64			ENSP00000508201.1		A0A804HL50

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.000291

AC:

AN:

247584

Hom.:

AF XY:

0.000305

AC XY:

AN XY:

134396

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.000883

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.000839

GnomAD4 exome

AF:

0.000264

AC:

385

AN:

1460140

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

726296

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000944

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000945

GnomAD4 genome

AF:

0.000466

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 24, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3122 of the FRAS1 protein (p.Arg3122Trp). This variant is present in population databases (rs200346497, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of Frasier syndrome (PMID: 24700879). ClinVar contains an entry for this variant (Variation ID: 198324). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FRAS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2023

Variant summary: FRAS1 c.9364C>T (p.Arg3122Trp) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 (IPR003644) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 247584 control chromosomes, predominantly at a frequency of 0.00088 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FRAS1 causing Cryptophthalmos Syndrome (0.00029 vs 0.0018), allowing no conclusion about variant significance. c.9364C>T has been reported in the literature as a single heterozygous change in individuals affected with isolated congenital anomalies of the kidney and urinary tract, without strong evidence for causality (example, Kohl_2014, Seltzsam_2022, Wang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24700879, 34906515, 31308072). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.9364C>T (p.R3122W) alteration is located in exon 62 (coding exon 62) of the FRAS1 gene. This alteration results from a C to T substitution at nucleotide position 9364, causing the arginine (R) at amino acid position 3122 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

FRAS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

The FRAS1 c.9364C>T variant is predicted to result in the amino acid substitution p.Arg3122Trp. This variant was reported in an individual with congenital anomalies of kidney and urinary tract along with a second potentially causative variant (Kohl et al. 2014. PubMed ID: 24700879; Table S6, Seltzsam et al. 2021. PubMed ID: 34906515). This variant has also been reported in a patient with Peter's anomaly (Supplementary Data 3C, Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.098% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fraser syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.046

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.92

PrimateAI

Pathogenic

0.86

Sift4G

Uncertain

0.0050

Vest4

0.93

MVP

0.69

ClinPred

0.10

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over