chr9-14801712-C-A

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.3634G>T(p.Ala1212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,613,200 control chromosomes in the GnomAD database, including 97,219 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 0.28 ( 7126 hom., cov: 32)

Exomes 𝑓: 0.35 ( 90093 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.565

Publications

29 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=0.002292037).

BP6

Variant 9-14801712-C-A is Benign according to our data. Variant chr9-14801712-C-A is described in ClinVar as Benign. ClinVar VariationId is 262537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.3634G>T	p.Ala1212Ser	missense_variant	Exon 20 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.3634G>T	p.Ala1212Ser	missense_variant	Exon 20 of 37	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7 link	n.3634G>T		non_coding_transcript_exon_variant	Exon 21 of 31	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43279

AN:

152016

Hom.:

7114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.531

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.345

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.349

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.299

GnomAD2 exomes

AF:

0.335

AC:

83429

AN:

249200

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.447

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.347

AC:

506735

AN:

1461064

Hom.:

90093

Cov.:

AF XY:

0.348

AC XY:

252758

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.106

AC:

3548

AN:

33476

American (AMR)

AF:

0.439

AC:

19654

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

9104

AN:

26128

East Asian (EAS)

AF:

0.224

AC:

8912

AN:

39700

South Asian (SAS)

AF:

0.337

AC:

29042

AN:

86244

European-Finnish (FIN)

AF:

0.327

AC:

17476

AN:

53402

Middle Eastern (MID)

AF:

0.322

AC:

1859

AN:

5766

European-Non Finnish (NFE)

AF:

0.357

AC:

396827

AN:

1111272

Other (OTH)

AF:

0.337

AC:

20313

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

16221

32441

48662

64882

81103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12538

25076

37614

50152

62690

<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:

0.285

AC:

43316

AN:

152136

Hom.:

7126

Cov.:

AF XY:

0.287

AC XY:

21370

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.118

AC:

4913

AN:

41532

American (AMR)

AF:

0.374

AC:

5719

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

1179

AN:

3468

East Asian (EAS)

AF:

0.207

AC:

1071

AN:

5168

South Asian (SAS)

AF:

0.346

AC:

1668

AN:

4816

European-Finnish (FIN)

AF:

0.325

AC:

3436

AN:

10570

Middle Eastern (MID)

AF:

0.360

AC:

105

AN:

292

European-Non Finnish (NFE)

AF:

0.354

AC:

24094

AN:

67980

Other (OTH)

AF:

0.307

AC:

648

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1524

3048

4571

6095

7619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.327

Hom.:

20058

Bravo

AF:

0.282

TwinsUK

AF:

0.345

AC:

1279

ALSPAC

AF:

0.357

AC:

1375

ESP6500AA

AF:

0.119

AC:

472

ESP6500EA

AF:

0.338

AC:

2824

ExAC

AF:

0.324

AC:

39173

Asia WGS

AF:

0.327

AC:

1137

AN:

3478

EpiCase

AF:

0.365

EpiControl

AF:

0.363

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Apr 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculotrichoanal syndrome

Benign:1

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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.5

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.044

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.71

T;.

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

L;L

PhyloP100

0.56

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.77

N;N

REVEL

Benign

0.021

Sift

Benign

0.66

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.0030

B;B

Vest4

0.15

ClinPred

0.0034

GERP RS

1.8

Varity_R

0.057

gMVP

0.35

Mutation Taster

=99/1

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