9-14842660-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001379081.2(FREM1):c.1394G>C(p.Gly465Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0127 in 1,610,642 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 24 hom., cov: 33)

Exomes 𝑓: 0.013 ( 274 hom. )

Consequence

FREM1
NM_001379081.2 missense, splice_region

Scores

Splicing: ADA: 0.7675

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.69

Publications

13 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007178992).

BP6

Variant 9-14842660-C-G is Benign according to our data. Variant chr9-14842660-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218939.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.012 (1829/152294) while in subpopulation SAS AF = 0.0435 (210/4830). AF 95% confidence interval is 0.0387. There are 24 homozygotes in GnomAd4. There are 947 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.1394G>C	p.Gly465Ala	missense_variant, splice_region_variant	Exon 9 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.1394G>C	p.Gly465Ala	missense_variant, splice_region_variant	Exon 9 of 37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1
FREM1	ENST00000380875.7 link	n.1394G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 31	1		ENSP00000370257.3		F8WE85

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1817

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0189

Gnomad SAS

AF:

0.0443

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00953

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0191

AC:

4667

AN:

244410

AF XY:

0.0196

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0425

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.000914

Gnomad NFE exome

AF:

0.00981

Gnomad OTH exome

AF:

0.0177

GnomAD4 exome

AF:

0.0128

AC:

18629

AN:

1458348

Hom.:

274

Cov.:

AF XY:

0.0137

AC XY:

9945

AN XY:

725328

show subpopulations

African (AFR)

AF:

0.0119

AC:

399

AN:

33438

American (AMR)

AF:

0.0401

AC:

1793

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

26022

East Asian (EAS)

AF:

0.0165

AC:

656

AN:

39680

South Asian (SAS)

AF:

0.0475

AC:

4082

AN:

86016

European-Finnish (FIN)

AF:

0.000985

AC:

AN:

52806

Middle Eastern (MID)

AF:

0.0290

AC:

164

AN:

5646

European-Non Finnish (NFE)

AF:

0.00949

AC:

10528

AN:

1109800

Other (OTH)

AF:

0.0150

AC:

901

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

895

1790

2686

3581

4476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.0120

AC:

1829

AN:

152294

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

947

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0109

AC:

455

AN:

41558

American (AMR)

AF:

0.0192

AC:

294

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.0187

AC:

AN:

5186

South Asian (SAS)

AF:

0.0435

AC:

210

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00953

AC:

648

AN:

68016

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0120

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.0103

AC:

ESP6500EA

AF:

0.00971

AC:

ExAC

AF:

0.0181

AC:

2193

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FREM1: BS1, BS2 -

Congenital diaphragmatic hernia

Uncertain:1

Mar 03, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. -

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 12, 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

0.15

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.

M_CAP

Benign

0.051

MetaRNN

Benign

0.0072

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

4.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;D

Vest4

0.57

ClinPred

0.034

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.71

Mutation Taster

=59/41

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.77

dbscSNV1_RF

Benign

0.58

SpliceAI score (max)

0.020

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