Variant summary

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

The ENST00000380880.4(FREM1):c.4791T>C(p.Asp1597Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,082 control chromosomes in the GnomAD database, including 615,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 55966 hom., cov: 32)

Exomes 𝑓: 0.88 ( 559915 hom. )

Consequence

FREM1
ENST00000380880.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0120

Publications

26 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=-0.84).

BP6

Variant 9-14775855-A-G is Benign according to our data. Variant chr9-14775855-A-G is described in ClinVar as Benign. ClinVar VariationId is 262542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380880.4. 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.4791T>C	p.Asp1597Asp	synonymous	Exon 25 of 37	NP_001366010.1
FREM1	NM_144966.7		c.4791T>C	p.Asp1597Asp	synonymous	Exon 26 of 38	NP_659403.4
FREM1	NM_001177704.3		c.399T>C	p.Asp133Asp	synonymous	Exon 2 of 14	NP_001171175.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FREM1	ENST00000380880.4	TSL:5 MANE Select	c.4791T>C	p.Asp1597Asp	synonymous	Exon 25 of 37	ENSP00000370262.3
FREM1	ENST00000380894.5	TSL:1	c.399T>C	p.Asp133Asp	synonymous	Exon 2 of 14	ENSP00000370278.1
FREM1	ENST00000380875.7	TSL:1	n.3981+16888T>C		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.857

AC:

130176

AN:

151914

Hom.:

55942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.795

Gnomad AMI

AF:

0.683

Gnomad AMR

AF:

0.875

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

0.858

Gnomad SAS

AF:

0.857

Gnomad FIN

AF:

0.910

Gnomad MID

AF:

0.883

Gnomad NFE

AF:

0.882

Gnomad OTH

AF:

0.872

GnomAD2 exomes

AF:

0.870

AC:

216627

AN:

249084

AF XY:

0.872

show subpopulations

Gnomad AFR exome

AF:

0.796

Gnomad AMR exome

AF:

0.834

Gnomad ASJ exome

AF:

0.897

Gnomad EAS exome

AF:

0.870

Gnomad FIN exome

AF:

0.910

Gnomad NFE exome

AF:

0.881

Gnomad OTH exome

AF:

0.869

GnomAD4 exome

AF:

0.875

AC:

1278506

AN:

1461050

Hom.:

559915

Cov.:

AF XY:

0.876

AC XY:

636352

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.799

AC:

26746

AN:

33460

American (AMR)

AF:

0.838

AC:

37472

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.894

AC:

23354

AN:

26136

East Asian (EAS)

AF:

0.842

AC:

33414

AN:

39694

South Asian (SAS)

AF:

0.867

AC:

74731

AN:

86244

European-Finnish (FIN)

AF:

0.907

AC:

48447

AN:

53400

Middle Eastern (MID)

AF:

0.882

AC:

5086

AN:

5768

European-Non Finnish (NFE)

AF:

0.879

AC:

976695

AN:

1111280

Other (OTH)

AF:

0.871

AC:

52561

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

8115

16230

24345

32460

40575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21306

42612

63918

85224

106530

<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:

0.857

AC:

130253

AN:

152032

Hom.:

55966

Cov.:

AF XY:

0.858

AC XY:

63786

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.795

AC:

32937

AN:

41440

American (AMR)

AF:

0.875

AC:

13369

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.893

AC:

3099

AN:

3472

East Asian (EAS)

AF:

0.857

AC:

4440

AN:

5178

South Asian (SAS)

AF:

0.857

AC:

4131

AN:

4822

European-Finnish (FIN)

AF:

0.910

AC:

9619

AN:

10574

Middle Eastern (MID)

AF:

0.874

AC:

257

AN:

294

European-Non Finnish (NFE)

AF:

0.882

AC:

59958

AN:

67954

Other (OTH)

AF:

0.866

AC:

1823

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

941

1882

2823

3764

4705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.876

Hom.:

98495

Bravo

AF:

0.851

Asia WGS

AF:

0.803

AC:

2793

AN:

3478

EpiCase

AF:

0.879

EpiControl

AF:

0.882

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Oculotrichoanal syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.8

(source)

DANN

Benign

0.34

PhyloP100

-0.012

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over