9-14846038-C-G

Position:

chr9-14846038-C-G

Variant summary

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

The NM_001379081.2(FREM1):c.1315G>C(p.Val439Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,605,884 control chromosomes in the GnomAD database, including 290,110 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23862 hom., cov: 33)

Exomes 𝑓: 0.60 ( 266248 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.30

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:

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=3.6315664E-6).

BP6

Variant 9-14846038-C-G is Benign according to our data. Variant chr9-14846038-C-G is described in ClinVar as [Benign]. Clinvar id is 262534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14846038-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2 linkuse as main transcript	c.1315G>C	p.Val439Leu	missense_variant	8/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4 linkuse as main transcript	c.1315G>C	p.Val439Leu	missense_variant	8/37	5	NM_001379081.2	P1	Q5H8C1-1
FREM1	ENST00000380875.7 linkuse as main transcript	c.1315G>C	p.Val439Leu	missense_variant, NMD_transcript_variant	9/31	1

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

84213

AN:

151968

Hom.:

23857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.481

Gnomad AMI

AF:

0.600

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.626

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.635

Gnomad FIN

AF:

0.596

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.544

GnomAD3 exomes

AF:

0.557

AC:

132436

AN:

237640

Hom.:

38211

AF XY:

0.570

AC XY:

73280

AN XY:

128586

show subpopulations

Gnomad AFR exome

AF:

0.474

Gnomad AMR exome

AF:

0.426

Gnomad ASJ exome

AF:

0.614

Gnomad EAS exome

AF:

0.268

Gnomad SAS exome

AF:

0.647

Gnomad FIN exome

AF:

0.606

Gnomad NFE exome

AF:

0.616

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.601

AC:

873081

AN:

1453798

Hom.:

266248

Cov.:

AF XY:

0.603

AC XY:

435673

AN XY:

722526

show subpopulations

Gnomad4 AFR exome

AF:

0.473

Gnomad4 AMR exome

AF:

0.435

Gnomad4 ASJ exome

AF:

0.613

Gnomad4 EAS exome

AF:

0.275

Gnomad4 SAS exome

AF:

0.646

Gnomad4 FIN exome

AF:

0.614

Gnomad4 NFE exome

AF:

0.620

Gnomad4 OTH exome

AF:

0.580

GnomAD4 genome

AF:

0.554

AC:

84238

AN:

152086

Hom.:

23862

Cov.:

AF XY:

0.552

AC XY:

41066

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.480

Gnomad4 AMR

AF:

0.499

Gnomad4 ASJ

AF:

0.626

Gnomad4 EAS

AF:

0.269

Gnomad4 SAS

AF:

0.637

Gnomad4 FIN

AF:

0.596

Gnomad4 NFE

AF:

0.616

Gnomad4 OTH

AF:

0.538

Alfa

AF:

0.575

Hom.:

7018

Bravo

AF:

0.538

TwinsUK

AF:

0.632

AC:

2343

ALSPAC

AF:

0.626

AC:

2413

ESP6500AA

AF:

0.487

AC:

2038

ESP6500EA

AF:

0.607

AC:

5134

ExAC

AF:

0.556

AC:

67235

Asia WGS

AF:

0.442

AC:

1542

AN:

3478

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Oculotrichoanal syndrome

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.7

DANN

Benign

0.86

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.93

D;.

MetaRNN

Benign

0.0000036

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.64

N;N

MutationTaster

Benign

0.48

P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.029

Sift

Benign

0.16

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.012

B;B

Vest4

0.19

ClinPred

0.0035

GERP RS

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.36

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