9-14747414-A-G

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.5859T>C(p.Val1953Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,611,672 control chromosomes in the GnomAD database, including 29,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2034 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27232 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0300

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=-0.84).

BP6

Variant 9-14747414-A-G is Benign according to our data. Variant chr9-14747414-A-G is described in ClinVar as [Benign]. Clinvar id is 262544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14747414-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.5859T>C	p.Val1953Val	synonymous_variant	Exon 33 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.5859T>C	p.Val1953Val	synonymous_variant	Exon 33 of 37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22414

AN:

151896

Hom.:

2035

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.174

AC:

43346

AN:

248528

Hom.:

4057

AF XY:

0.174

AC XY:

23405

AN XY:

134838

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.163

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.189

AC:

276192

AN:

1459658

Hom.:

27232

Cov.:

AF XY:

0.188

AC XY:

136476

AN XY:

726222

show subpopulations

Gnomad4 AFR exome

AF:

0.0293

Gnomad4 AMR exome

AF:

0.189

Gnomad4 ASJ exome

AF:

0.147

Gnomad4 EAS exome

AF:

0.219

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.196

Gnomad4 NFE exome

AF:

0.196

Gnomad4 OTH exome

AF:

0.183

GnomAD4 genome

AF:

0.147

AC:

22414

AN:

152014

Hom.:

2034

Cov.:

AF XY:

0.147

AC XY:

10907

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0350

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.142

Gnomad4 EAS

AF:

0.192

Gnomad4 SAS

AF:

0.158

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.197

Gnomad4 OTH

AF:

0.169

Alfa

AF:

0.183

Hom.:

4417

Bravo

AF:

0.142

Asia WGS

AF:

0.186

AC:

651

AN:

3478

EpiCase

AF:

0.179

EpiControl

AF:

0.179

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

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

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculotrichoanal syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

DANN

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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