Genetic Variant FREM1:p.Ala1539Ala (chr9-14776029-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_144966.7(FREM1):c.4617G>A(p.Ala1539Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,790 control chromosomes in the GnomAD database, including 21,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1766 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19717 hom. )

Consequence

FREM1
NM_144966.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.39

Publications

14 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=-0.75).

BP6

Variant 9-14776029-C-T is Benign according to our data. Variant chr9-14776029-C-T is described in ClinVar as Benign. ClinVar VariationId is 262539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144966.7. 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.4617G>A	p.Ala1539Ala	synonymous	Exon 25 of 37	NP_001366010.1
FREM1	NM_144966.7		c.4617G>A	p.Ala1539Ala	synonymous	Exon 26 of 38	NP_659403.4
FREM1	NM_001177704.3		c.225G>A	p.Ala75Ala	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.4617G>A	p.Ala1539Ala	synonymous	Exon 25 of 37	ENSP00000370262.3
FREM1	ENST00000380894.5	TSL:1	c.225G>A	p.Ala75Ala	synonymous	Exon 2 of 14	ENSP00000370278.1
FREM1	ENST00000380875.7	TSL:1	n.3981+16714G>A		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21694

AN:

152054

Hom.:

1762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.0280

Gnomad SAS

AF:

0.0852

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.150

GnomAD2 exomes

AF:

0.131

AC:

32500

AN:

248776

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.0787

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.0261

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.159

AC:

232908

AN:

1461618

Hom.:

19717

Cov.:

AF XY:

0.157

AC XY:

114494

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.136

AC:

4551

AN:

33478

American (AMR)

AF:

0.0842

AC:

3764

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3577

AN:

26136

East Asian (EAS)

AF:

0.0240

AC:

954

AN:

39696

South Asian (SAS)

AF:

0.0882

AC:

7606

AN:

86258

European-Finnish (FIN)

AF:

0.131

AC:

6978

AN:

53400

Middle Eastern (MID)

AF:

0.130

AC:

751

AN:

5768

European-Non Finnish (NFE)

AF:

0.176

AC:

195698

AN:

1111784

Other (OTH)

AF:

0.150

AC:

9029

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

11477

22954

34431

45908

57385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6824

13648

20472

27296

34120

<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:

0.143

AC:

21704

AN:

152172

Hom.:

1766

Cov.:

AF XY:

0.138

AC XY:

10283

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.134

AC:

5572

AN:

41520

American (AMR)

AF:

0.120

AC:

1839

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

452

AN:

3470

East Asian (EAS)

AF:

0.0281

AC:

145

AN:

5168

South Asian (SAS)

AF:

0.0852

AC:

411

AN:

4822

European-Finnish (FIN)

AF:

0.124

AC:

1318

AN:

10606

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11538

AN:

67984

Other (OTH)

AF:

0.147

AC:

310

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

975

1950

2925

3900

4875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.156

Hom.:

959

Bravo

AF:

0.142

Asia WGS

AF:

0.0550

AC:

194

AN:

3478

EpiCase

AF:

0.177

EpiControl

AF:

0.172

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Oculotrichoanal syndrome (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.70

(source)

DANN

Benign

0.34

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over