NM_001379081.2:c.829-12A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379081.2(FREM1):c.829-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,590,922 control chromosomes in the GnomAD database, including 507,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42656 hom., cov: 31)

Exomes 𝑓: 0.80 ( 465066 hom. )

Consequence

FREM1
NM_001379081.2 intron

Scores

Splicing: ADA: 0.00001803

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0320

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-14851619-T-C is Benign according to our data. Variant chr9-14851619-T-C is described in ClinVar as [Benign]. Clinvar id is 262546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14851619-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.829-12A>G		intron_variant	Intron 5 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4 link	c.829-12A>G		intron_variant	Intron 5 of 36	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1
FREM1	ENST00000380875.7 link	n.829-12A>G		intron_variant	Intron 6 of 30	1		ENSP00000370257.3		F8WE85

Frequencies

GnomAD3 genomes

AF:

0.739

AC:

112241

AN:

151930

Hom.:

42632

Cov.:

show subpopulations

Gnomad AFR

AF:

0.545

Gnomad AMI

AF:

0.654

Gnomad AMR

AF:

0.778

Gnomad ASJ

AF:

0.823

Gnomad EAS

AF:

0.962

Gnomad SAS

AF:

0.861

Gnomad FIN

AF:

0.869

Gnomad MID

AF:

0.747

Gnomad NFE

AF:

0.798

Gnomad OTH

AF:

0.757

GnomAD3 exomes

AF:

0.809

AC:

200598

AN:

247918

Hom.:

82055

AF XY:

0.815

AC XY:

109700

AN XY:

134614

show subpopulations

Gnomad AFR exome

AF:

0.533

Gnomad AMR exome

AF:

0.798

Gnomad ASJ exome

AF:

0.825

Gnomad EAS exome

AF:

0.965

Gnomad SAS exome

AF:

0.868

Gnomad FIN exome

AF:

0.863

Gnomad NFE exome

AF:

0.798

Gnomad OTH exome

AF:

0.801

GnomAD4 exome

AF:

0.802

AC:

1154022

AN:

1438874

Hom.:

465066

Cov.:

AF XY:

0.805

AC XY:

577443

AN XY:

717470

show subpopulations

Gnomad4 AFR exome

AF:

0.544

Gnomad4 AMR exome

AF:

0.797

Gnomad4 ASJ exome

AF:

0.826

Gnomad4 EAS exome

AF:

0.964

Gnomad4 SAS exome

AF:

0.867

Gnomad4 FIN exome

AF:

0.860

Gnomad4 NFE exome

AF:

0.796

Gnomad4 OTH exome

AF:

0.799

GnomAD4 genome

AF:

0.739

AC:

112314

AN:

152048

Hom.:

42656

Cov.:

AF XY:

0.747

AC XY:

55511

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.545

Gnomad4 AMR

AF:

0.778

Gnomad4 ASJ

AF:

0.823

Gnomad4 EAS

AF:

0.962

Gnomad4 SAS

AF:

0.862

Gnomad4 FIN

AF:

0.869

Gnomad4 NFE

AF:

0.798

Gnomad4 OTH

AF:

0.760

Alfa

AF:

0.785

Hom.:

50045

Bravo

AF:

0.722

Asia WGS

AF:

0.872

AC:

3036

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 21, 2020

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.13

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