9-14819372-G-T

Position:

chr9-14819372-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379081.2(FREM1):c.2408C>A(p.Ser803Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,612,312 control chromosomes in the GnomAD database, including 44,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3471 hom., cov: 33)

Exomes 𝑓: 0.23 ( 41008 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.51

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 links:

FREM1 (HGNC:):

FREM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020454526).

BP6

Variant 9-14819372-G-T is Benign according to our data. Variant chr9-14819372-G-T is described in ClinVar as [Benign]. Clinvar id is 262535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14819372-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM1	NM_001379081.2 linkuse as main transcript	c.2408C>A	p.Ser803Tyr	missense_variant	14/37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4 linkuse as main transcript	c.2408C>A	p.Ser803Tyr	missense_variant	14/37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1
FREM1	ENST00000380875.7 linkuse as main transcript	n.2408C>A		non_coding_transcript_exon_variant	15/31	1		ENSP00000370257.3		F8WE85

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30703

AN:

152086

Hom.:

3472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.0893

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.239

GnomAD3 exomes

AF:

0.231

AC:

57314

AN:

248550

Hom.:

6949

AF XY:

0.230

AC XY:

31051

AN XY:

134826

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.290

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.0973

Gnomad SAS exome

AF:

0.221

Gnomad FIN exome

AF:

0.241

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.239

GnomAD4 exome

AF:

0.233

AC:

340296

AN:

1460108

Hom.:

41008

Cov.:

AF XY:

0.233

AC XY:

169321

AN XY:

726396

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.283

Gnomad4 ASJ exome

AF:

0.270

Gnomad4 EAS exome

AF:

0.0948

Gnomad4 SAS exome

AF:

0.223

Gnomad4 FIN exome

AF:

0.238

Gnomad4 NFE exome

AF:

0.239

Gnomad4 OTH exome

AF:

0.226

GnomAD4 genome

AF:

0.202

AC:

30704

AN:

152204

Hom.:

3471

Cov.:

AF XY:

0.201

AC XY:

14962

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.254

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.0894

Gnomad4 SAS

AF:

0.201

Gnomad4 FIN

AF:

0.244

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.229

Hom.:

10332

Bravo

AF:

0.200

TwinsUK

AF:

0.248

AC:

920

ALSPAC

AF:

0.245

AC:

943

ESP6500AA

AF:

0.117

AC:

455

ESP6500EA

AF:

0.247

AC:

2046

ExAC

AF:

0.229

AC:

27633

Asia WGS

AF:

0.160

AC:

558

AN:

3478

EpiCase

AF:

0.242

EpiControl

AF:

0.247

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Oculotrichoanal syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

D;.

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.043

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.56

ClinPred

0.038

GERP RS

5.9

Varity_R

0.45

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over