NM_001379081.2:c.6428A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379081.2(FREM1):c.6428A>C(p.Gln2143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,612,218 control chromosomes in the GnomAD database, including 431,661 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42516 hom., cov: 31)

Exomes 𝑓: 0.73 ( 389145 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.576

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

oculotrichoanal syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
BNAR syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
isolated trigonocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
trigonocephaly 2
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

FREM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3810069E-6).

BP6

Variant 9-14737508-T-G is Benign according to our data. Variant chr9-14737508-T-G is described in ClinVar as Benign. ClinVar VariationId is 262545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379081.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FREM1	NM_001379081.2	MANE Select	c.6428A>C	p.Gln2143Pro	missense	Exon 37 of 37	NP_001366010.1
FREM1	NM_144966.7		c.6428A>C	p.Gln2143Pro	missense	Exon 38 of 38	NP_659403.4
FREM1	NM_001177704.3		c.2036A>C	p.Gln679Pro	missense	Exon 14 of 14	NP_001171175.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FREM1	ENST00000380880.4	TSL:5 MANE Select	c.6428A>C	p.Gln2143Pro	missense	Exon 37 of 37	ENSP00000370262.3
FREM1	ENST00000380894.5	TSL:1	c.2036A>C	p.Gln679Pro	missense	Exon 14 of 14	ENSP00000370278.1
FREM1	ENST00000380875.7	TSL:1	n.*994A>C		non_coding_transcript_exon	Exon 31 of 31	ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113483

AN:

151860

Hom.:

42495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.709

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.827

Gnomad EAS

AF:

0.775

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.807

Gnomad NFE

AF:

0.730

Gnomad OTH

AF:

0.752

GnomAD2 exomes

AF:

0.735

AC:

181690

AN:

247034

AF XY:

0.731

show subpopulations

Gnomad AFR exome

AF:

0.790

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.830

Gnomad EAS exome

AF:

0.776

Gnomad FIN exome

AF:

0.702

Gnomad NFE exome

AF:

0.738

Gnomad OTH exome

AF:

0.748

GnomAD4 exome

AF:

0.729

AC:

1064555

AN:

1460238

Hom.:

389145

Cov.:

AF XY:

0.727

AC XY:

528254

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.787

AC:

26327

AN:

33462

American (AMR)

AF:

0.754

AC:

33611

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

21645

AN:

26100

East Asian (EAS)

AF:

0.721

AC:

28582

AN:

39656

South Asian (SAS)

AF:

0.647

AC:

55717

AN:

86074

European-Finnish (FIN)

AF:

0.699

AC:

37277

AN:

53322

Middle Eastern (MID)

AF:

0.799

AC:

4605

AN:

5766

European-Non Finnish (NFE)

AF:

0.731

AC:

812275

AN:

1110988

Other (OTH)

AF:

0.738

AC:

44516

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

14728

29456

44184

58912

73640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20082

40164

60246

80328

100410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.747

AC:

113560

AN:

151980

Hom.:

42516

Cov.:

AF XY:

0.745

AC XY:

55341

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.786

AC:

32560

AN:

41430

American (AMR)

AF:

0.751

AC:

11468

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.827

AC:

2869

AN:

3470

East Asian (EAS)

AF:

0.775

AC:

3994

AN:

5154

South Asian (SAS)

AF:

0.650

AC:

3123

AN:

4802

European-Finnish (FIN)

AF:

0.707

AC:

7460

AN:

10552

Middle Eastern (MID)

AF:

0.803

AC:

236

AN:

294

European-Non Finnish (NFE)

AF:

0.730

AC:

49618

AN:

67984

Other (OTH)

AF:

0.752

AC:

1587

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1465

2930

4394

5859

7324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.739

Hom.:

200619

Bravo

AF:

0.756

TwinsUK

AF:

0.720

AC:

2670

ALSPAC

AF:

0.741

AC:

2854

ESP6500AA

AF:

0.793

AC:

3022

ESP6500EA

AF:

0.734

AC:

6057

ExAC

AF:

0.732

AC:

88386

Asia WGS

AF:

0.686

AC:

2385

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oculotrichoanal syndrome

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

May 04, 2021

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.9

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.040

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PhyloP100

-0.58

PrimateAI

Benign

0.25

PROVEAN

Benign

0.090

REVEL

Benign

0.016

Sift

Benign

0.31

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.13

ClinPred

0.00098

GERP RS

-0.73

Varity_R

0.15

gMVP

0.84

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over