9-14775919-T-A

Position:

chr9-14775919-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379081.2(FREM1):c.4727A>T(p.Asn1576Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,978 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 72 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.835

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=0.00500378).

BP6

Variant 9-14775919-T-A is Benign according to our data. Variant chr9-14775919-T-A is described in ClinVar as [Benign]. Clinvar id is 262540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14775919-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00613 (934/152280) while in subpopulation AMR AF= 0.0434 (664/15298). AF 95% confidence interval is 0.0407. There are 25 homozygotes in gnomad4. There are 534 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM1	NM_001379081.2 linkuse as main transcript	c.4727A>T	p.Asn1576Ile	missense_variant	25/37	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.4727A>T	p.Asn1576Ile	missense_variant	25/37	5	NM_001379081.2	ENSP00000370262	P1	Q5H8C1-1

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

931

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0434

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00928

AC:

2311

AN:

249070

Hom.:

AF XY:

0.00735

AC XY:

993

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.0523

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00122

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.00612

GnomAD4 exome

AF:

0.00396

AC:

5784

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

2666

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0491

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00307

Gnomad4 SAS exome

AF:

0.00305

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00268

Gnomad4 OTH exome

AF:

0.00267

GnomAD4 genome

AF:

0.00613

AC:

934

AN:

152280

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0434

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00315

Hom.:

Bravo

AF:

0.00800

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00124

AC:

ESP6500EA

AF:

0.00274

AC:

ExAC

AF:

0.00705

AC:

853

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Oculotrichoanal syndrome

Benign:1

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

0.14

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.052

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.72

T;T;.

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.4

N;D;N

REVEL

Benign

0.053

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.087

T;D;T

Polyphen

0.17

B;.;B

Vest4

0.30

MVP

0.11

ClinPred

0.0074

GERP RS

-5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

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