rs10810249

Positions:

Variant summary

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

The NM_001379081.2(FREM1):c.3089-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,565,898 control chromosomes in the GnomAD database, including 42,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3329 hom., cov: 32)

Exomes 𝑓: 0.23 ( 38791 hom. )

Consequence

FREM1
NM_001379081.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000007089

Clinical Significance

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

Conservation

PhyloP100: -0.641

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 (BayesDel_noAF=-0.52).

BP6

Variant 9-14806850-C-A is Benign according to our data. Variant chr9-14806850-C-A is described in ClinVar as [Benign]. Clinvar id is 262536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14806850-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.245 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.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		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.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001379081.2	ENSP00000370262	P1	Q5H8C1-1
FREM1	ENST00000380875.7 linkuse as main transcript	c.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000370257

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29248

AN:

151998

Hom.:

3329

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0766

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.252

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.0882

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.231

GnomAD3 exomes

AF:

0.228

AC:

49526

AN:

216886

Hom.:

5851

AF XY:

0.228

AC XY:

26685

AN XY:

116810

show subpopulations

Gnomad AFR exome

AF:

0.0711

Gnomad AMR exome

AF:

0.292

Gnomad ASJ exome

AF:

0.274

Gnomad EAS exome

AF:

0.0997

Gnomad SAS exome

AF:

0.221

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.229

AC:

324234

AN:

1413782

Hom.:

38791

Cov.:

AF XY:

0.230

AC XY:

161039

AN XY:

701640

show subpopulations

Gnomad4 AFR exome

AF:

0.0718

Gnomad4 AMR exome

AF:

0.282

Gnomad4 ASJ exome

AF:

0.269

Gnomad4 EAS exome

AF:

0.0964

Gnomad4 SAS exome

AF:

0.219

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.221

GnomAD4 genome

AF:

0.192

AC:

29249

AN:

152116

Hom.:

3329

Cov.:

AF XY:

0.192

AC XY:

14278

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0765

Gnomad4 AMR

AF:

0.252

Gnomad4 ASJ

AF:

0.263

Gnomad4 EAS

AF:

0.0882

Gnomad4 SAS

AF:

0.197

Gnomad4 FIN

AF:

0.248

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.204

Hom.:

1524

Bravo

AF:

0.190

Asia WGS

AF:

0.151

AC:

528

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.2

DANN

Benign

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000071

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.040

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