9-14859358-T-C

Variant names:

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.456A>G(p.Gln152Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,536 control chromosomes in the GnomAD database, including 29,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3139 hom., cov: 32)

Exomes 𝑓: 0.17 ( 26803 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0370

Publications

21 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=-0.85).

BP6

Variant 9-14859358-T-C is Benign according to our data. Variant chr9-14859358-T-C is described in ClinVar as Benign. ClinVar VariationId is 366172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.037 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.456A>G	p.Gln152Gln	synonymous_variant	Exon 4 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.456A>G	p.Gln152Gln	synonymous_variant	Exon 4 of 37	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7 link	n.456A>G		non_coding_transcript_exon_variant	Exon 5 of 31	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27909

AN:

151924

Hom.:

3136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.260

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.177

GnomAD2 exomes

AF:

0.218

AC:

54438

AN:

249218

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.337

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.557

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.175

AC:

255347

AN:

1461494

Hom.:

26803

Cov.:

AF XY:

0.173

AC XY:

125998

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.150

AC:

5008

AN:

33478

American (AMR)

AF:

0.325

AC:

14526

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

4751

AN:

26132

East Asian (EAS)

AF:

0.573

AC:

22738

AN:

39688

South Asian (SAS)

AF:

0.168

AC:

14486

AN:

86252

European-Finnish (FIN)

AF:

0.226

AC:

12078

AN:

53402

Middle Eastern (MID)

AF:

0.155

AC:

893

AN:

5768

European-Non Finnish (NFE)

AF:

0.152

AC:

169492

AN:

1111684

Other (OTH)

AF:

0.188

AC:

11375

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

10946

21892

32838

43784

54730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6396

12792

19188

25584

31980

<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:

0.184

AC:

27927

AN:

152042

Hom.:

3139

Cov.:

AF XY:

0.192

AC XY:

14301

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.148

AC:

6157

AN:

41464

American (AMR)

AF:

0.260

AC:

3972

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

624

AN:

3472

East Asian (EAS)

AF:

0.555

AC:

2856

AN:

5146

South Asian (SAS)

AF:

0.175

AC:

838

AN:

4802

European-Finnish (FIN)

AF:

0.244

AC:

2585

AN:

10574

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.152

AC:

10303

AN:

67994

Other (OTH)

AF:

0.178

AC:

377

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1110

2220

3329

4439

5549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.157

Hom.:

1012

Bravo

AF:

0.190

Asia WGS

AF:

0.297

AC:

1033

AN:

3478

EpiCase

AF:

0.159

EpiControl

AF:

0.148

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 04, 2021

GeneDx

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.3

(source)

DANN

Benign

0.32

PhyloP100

-0.037

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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