Genetic Variant FREM1:c.1881+58G>C (chr9-14841389-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001379081.2(FREM1):c.1881+58G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,381,686 control chromosomes in the GnomAD database, including 32,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2627 hom., cov: 33)

Exomes 𝑓: 0.21 ( 30014 hom. )

Consequence

FREM1
NM_001379081.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.370

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 (BayesDel_noAF=-0.82).

BP6

Variant 9-14841389-C-G is Benign according to our data. Variant chr9-14841389-C-G is described in ClinVar as [Benign]. Clinvar id is 1258834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14841389-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.1881+58G>C		intron_variant	Intron 10 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4 link	c.1881+58G>C		intron_variant	Intron 10 of 36	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1
FREM1	ENST00000380875.7 link	n.1881+58G>C		intron_variant	Intron 11 of 30	1		ENSP00000370257.3		F8WE85

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25529

AN:

152058

Hom.:

2629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0643

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.0268

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.177

GnomAD4 exome

AF:

0.213

AC:

262402

AN:

1229510

Hom.:

30014

AF XY:

0.213

AC XY:

128360

AN XY:

603942

show subpopulations

Gnomad4 AFR exome

AF:

0.0569

Gnomad4 AMR exome

AF:

0.152

Gnomad4 ASJ exome

AF:

0.179

Gnomad4 EAS exome

AF:

0.0285

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.218

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.192

GnomAD4 genome

AF:

0.168

AC:

25528

AN:

152176

Hom.:

2627

Cov.:

AF XY:

0.165

AC XY:

12278

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0642

Gnomad4 AMR

AF:

0.172

Gnomad4 ASJ

AF:

0.176

Gnomad4 EAS

AF:

0.0268

Gnomad4 SAS

AF:

0.134

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.232

Gnomad4 OTH

AF:

0.174

Alfa

AF:

0.109

Hom.:

189

Bravo

AF:

0.160

Asia WGS

AF:

0.0790

AC:

275

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.7

DANN

Benign

0.63

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