rs2131880

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379081.2(FREM1):c.4617G>A(p.Ala1539Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,790 control chromosomes in the GnomAD database, including 21,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1766 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19717 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.39

Variant links:

Genes affected

FREM1 (HGNC:23399): (FRAS1 related extracellular matrix 1) This gene encodes a basement membrane protein that may play a role in craniofacial and renal development. Mutations in this gene have been associated with bifid nose with or without anorectal and renal anomalies. Alternatively spliced transcript variants encoding different isoforms have been described. PubMed ID 19940113 describes one such variant that initiates transcription within a distinct, internal exon; the resulting shorter isoform (named Toll-like/interleukin-1 receptor regulator, TILRR) is suggested to be a co-receptor of the interleukin 1 receptor family and may regulate receptor function and Toll-like receptor/interleukin 1 receptor signal transduction, contributing to the control of inflammatory response activation. [provided by RefSeq, Apr 2011]

FREM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 9-14776029-C-T is Benign according to our data. Variant chr9-14776029-C-T is described in ClinVar as [Benign]. Clinvar id is 262539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14776029-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 25 of 37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4 link	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 25 of 37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21694

AN:

152054

Hom.:

1762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.0280

Gnomad SAS

AF:

0.0852

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.131

AC:

32500

AN:

248776

Hom.:

2492

AF XY:

0.131

AC XY:

17674

AN XY:

134942

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.0787

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.0261

Gnomad SAS exome

AF:

0.0884

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.159

AC:

232908

AN:

1461618

Hom.:

19717

Cov.:

AF XY:

0.157

AC XY:

114494

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.0842

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.0240

Gnomad4 SAS exome

AF:

0.0882

Gnomad4 FIN exome

AF:

0.131

Gnomad4 NFE exome

AF:

0.176

Gnomad4 OTH exome

AF:

0.150

GnomAD4 genome

AF:

0.143

AC:

21704

AN:

152172

Hom.:

1766

Cov.:

AF XY:

0.138

AC XY:

10283

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.120

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.0281

Gnomad4 SAS

AF:

0.0852

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.157

Hom.:

954

Bravo

AF:

0.142

Asia WGS

AF:

0.0550

AC:

194

AN:

3478

EpiCase

AF:

0.177

EpiControl

AF:

0.172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oculotrichoanal syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.70

DANN

Benign

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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