rs10733289

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379081.2(FREM1):c.4785C>T(p.Ala1595Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,504 control chromosomes in the GnomAD database, including 249,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18981 hom., cov: 32)

Exomes 𝑓: 0.56 ( 230123 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.642

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 9-14775861-G-A is Benign according to our data. Variant chr9-14775861-G-A is described in ClinVar as Benign. ClinVar VariationId is 262541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.642 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.4785C>T	p.Ala1595Ala	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.4785C>T	p.Ala1595Ala	synonymous_variant	Exon 25 of 37	5	NM_001379081.2	ENSP00000370262.3

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73660

AN:

151880

Hom.:

18967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.584

Gnomad OTH

AF:

0.476

GnomAD2 exomes

AF:

0.506

AC:

126023

AN:

249074

AF XY:

0.511

show subpopulations

Gnomad AFR exome

AF:

0.332

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.505

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.626

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.509

GnomAD4 exome

AF:

0.556

AC:

811472

AN:

1460506

Hom.:

230123

Cov.:

AF XY:

0.553

AC XY:

402145

AN XY:

726564

show subpopulations

African (AFR)

AF:

0.324

AC:

10855

AN:

33462

American (AMR)

AF:

0.390

AC:

17459

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

13160

AN:

26134

East Asian (EAS)

AF:

0.297

AC:

11769

AN:

39692

South Asian (SAS)

AF:

0.485

AC:

41804

AN:

86242

European-Finnish (FIN)

AF:

0.627

AC:

33476

AN:

53402

Middle Eastern (MID)

AF:

0.391

AC:

2256

AN:

5766

European-Non Finnish (NFE)

AF:

0.585

AC:

649266

AN:

1110762

Other (OTH)

AF:

0.521

AC:

31427

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

17881

35761

53642

71522

89403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17634

35268

52902

70536

88170

<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:

0.485

AC:

73694

AN:

151998

Hom.:

18981

Cov.:

AF XY:

0.484

AC XY:

35957

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.333

AC:

13791

AN:

41442

American (AMR)

AF:

0.428

AC:

6550

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1731

AN:

3472

East Asian (EAS)

AF:

0.313

AC:

1617

AN:

5172

South Asian (SAS)

AF:

0.467

AC:

2248

AN:

4814

European-Finnish (FIN)

AF:

0.622

AC:

6560

AN:

10554

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.584

AC:

39674

AN:

67950

Other (OTH)

AF:

0.471

AC:

991

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1850

3700

5551

7401

9251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.528

Hom.:

37573

Bravo

AF:

0.459

Asia WGS

AF:

0.386

AC:

1347

AN:

3478

EpiCase

AF:

0.561

EpiControl

AF:

0.562

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 28, 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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.3

(source)

DANN

Benign

0.46

PhyloP100

0.64

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over