rs10738380

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.3657A>G(p.Ala1219Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,132 control chromosomes in the GnomAD database, including 41,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2961 hom., cov: 33)

Exomes 𝑓: 0.23 ( 38242 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.162

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=-0.83).

BP6

Variant 9-14801689-T-C is Benign according to our data. Variant chr9-14801689-T-C is described in ClinVar as [Benign]. Clinvar id is 262538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14801689-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.162 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.3657A>G	p.Ala1219Ala	synonymous_variant	Exon 20 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.3657A>G	p.Ala1219Ala	synonymous_variant	Exon 20 of 37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1
FREM1	ENST00000380875.7 link	n.3657A>G		non_coding_transcript_exon_variant	Exon 21 of 31	1		ENSP00000370257.3		F8WE85

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27554

AN:

152076

Hom.:

2962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0585

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.226

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.223

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.190

GnomAD3 exomes

AF:

0.218

AC:

54349

AN:

249116

Hom.:

6198

AF XY:

0.221

AC XY:

29805

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.0557

Gnomad AMR exome

AF:

0.214

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.231

Gnomad SAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.226

AC:

330683

AN:

1460938

Hom.:

38242

Cov.:

AF XY:

0.227

AC XY:

164743

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.0503

Gnomad4 AMR exome

AF:

0.213

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.211

Gnomad4 SAS exome

AF:

0.241

Gnomad4 FIN exome

AF:

0.223

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.215

GnomAD4 genome

AF:

0.181

AC:

27553

AN:

152194

Hom.:

2961

Cov.:

AF XY:

0.181

AC XY:

13490

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0582

Gnomad4 AMR

AF:

0.197

Gnomad4 ASJ

AF:

0.226

Gnomad4 EAS

AF:

0.215

Gnomad4 SAS

AF:

0.223

Gnomad4 FIN

AF:

0.226

Gnomad4 NFE

AF:

0.237

Gnomad4 OTH

AF:

0.188

Alfa

AF:

0.222

Hom.:

7501

Bravo

AF:

0.173

Asia WGS

AF:

0.217

AC:

755

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

May 18, 2020

GeneDx

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:1

Jan 12, 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

-0.83

CADD

Benign

0.79

DANN

Benign

0.51

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