chr9-14737508-T-G

Position:

chr9-14737508-T-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.6428A>C(p.Gln2143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,612,218 control chromosomes in the GnomAD database, including 431,661 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 0.75 ( 42516 hom., cov: 31)

Exomes 𝑓: 0.73 ( 389145 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.576

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3810069E-6).

BP6

Variant 9-14737508-T-G is Benign according to our data. Variant chr9-14737508-T-G is described in ClinVar as [Benign]. Clinvar id is 262545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14737508-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 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.6428A>C	p.Gln2143Pro	missense_variant	37/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4 linkuse as main transcript	c.6428A>C	p.Gln2143Pro	missense_variant	37/37	5	NM_001379081.2	P1	Q5H8C1-1
FREM1	ENST00000380894.5 linkuse as main transcript	c.2036A>C	p.Gln679Pro	missense_variant	14/14	1			Q5H8C1-2
FREM1	ENST00000380875.7 linkuse as main transcript	c.*994A>C		3_prime_UTR_variant, NMD_transcript_variant	31/31	1
FREM1	ENST00000427623.5 linkuse as main transcript	c.*609A>C		3_prime_UTR_variant, NMD_transcript_variant	11/11	5			Q5H8C1-4

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113483

AN:

151860

Hom.:

42495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.786

Gnomad AMI

AF:

0.709

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.827

Gnomad EAS

AF:

0.775

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.807

Gnomad NFE

AF:

0.730

Gnomad OTH

AF:

0.752

GnomAD3 exomes

AF:

0.735

AC:

181690

AN:

247034

Hom.:

66949

AF XY:

0.731

AC XY:

98028

AN XY:

134044

show subpopulations

Gnomad AFR exome

AF:

0.790

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.830

Gnomad EAS exome

AF:

0.776

Gnomad SAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.702

Gnomad NFE exome

AF:

0.738

Gnomad OTH exome

AF:

0.748

GnomAD4 exome

AF:

0.729

AC:

1064555

AN:

1460238

Hom.:

389145

Cov.:

AF XY:

0.727

AC XY:

528254

AN XY:

726350

show subpopulations

Gnomad4 AFR exome

AF:

0.787

Gnomad4 AMR exome

AF:

0.754

Gnomad4 ASJ exome

AF:

0.829

Gnomad4 EAS exome

AF:

0.721

Gnomad4 SAS exome

AF:

0.647

Gnomad4 FIN exome

AF:

0.699

Gnomad4 NFE exome

AF:

0.731

Gnomad4 OTH exome

AF:

0.738

GnomAD4 genome

AF:

0.747

AC:

113560

AN:

151980

Hom.:

42516

Cov.:

AF XY:

0.745

AC XY:

55341

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.786

Gnomad4 AMR

AF:

0.751

Gnomad4 ASJ

AF:

0.827

Gnomad4 EAS

AF:

0.775

Gnomad4 SAS

AF:

0.650

Gnomad4 FIN

AF:

0.707

Gnomad4 NFE

AF:

0.730

Gnomad4 OTH

AF:

0.752

Alfa

AF:

0.740

Hom.:

103245

Bravo

AF:

0.756

TwinsUK

AF:

0.720

AC:

2670

ALSPAC

AF:

0.741

AC:

2854

ESP6500AA

AF:

0.793

AC:

3022

ESP6500EA

AF:

0.734

AC:

6057

ExAC

AF:

0.732

AC:

88386

Asia WGS

AF:

0.686

AC:

2385

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	-	- -

Oculotrichoanal syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.9

DANN

Benign

0.78

DEOGEN2

Benign

0.040

T;.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

T;T;.

MetaRNN

Benign

0.0000014

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

L;.;L

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

0.090

N;N;N

REVEL

Benign

0.016

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.13

ClinPred

0.00098

GERP RS

-0.73

Varity_R

0.15

gMVP

0.84

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