chr9-14851619-T-C

Position:

• chr9-14851619-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379081.2(FREM1):​c.829-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,590,922 control chromosomes in the GnomAD database, including 507,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42656 hom., cov: 31)
  • Exomes 𝑓: 0.80 (465066 hom.)
• Consequence: FREM1 NM_001379081.2 intron
• Scores: Splicing: ADA: 0.00001803
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0320

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-14851619-T-C is Benign according to our data. Variant chr9-14851619-T-C is described in ClinVar as [Benign]. Clinvar id is 262546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14851619-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.829-12A>G		intron_variant		ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.829-12A>G		intron_variant		5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.829-12A>G		intron_variant		1		ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112241 AN: 151930 Hom.: 42632 Cov.: 31

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.757

GnomAD3 exomes AF: 0.809 AC: 200598 AN: 247918 Hom.: 82055 AF XY: 0.815 AC XY: 109700 AN XY: 134614

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.798

Gnomad ASJ exome AF: 0.825

Gnomad EAS exome AF: 0.965

Gnomad SAS exome AF: 0.868

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.798

Gnomad OTH exome AF: 0.801

GnomAD4 exome AF: 0.802 AC: 1154022 AN: 1438874 Hom.: 465066 Cov.: 27 AF XY: 0.805 AC XY: 577443 AN XY: 717470

Gnomad4 AFR exome AF: 0.544

Gnomad4 AMR exome AF: 0.797

Gnomad4 ASJ exome AF: 0.826

Gnomad4 EAS exome AF: 0.964

Gnomad4 SAS exome AF: 0.867

Gnomad4 FIN exome AF: 0.860

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.739 AC: 112314 AN: 152048 Hom.: 42656 Cov.: 31 AF XY: 0.747 AC XY: 55511 AN XY: 74352

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.823

Gnomad4 EAS AF: 0.962

Gnomad4 SAS AF: 0.862

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.798

Gnomad4 OTH AF: 0.760

Alfa AF: 0.785 Hom.: 50045

Bravo AF: 0.722

Asia WGS AF: 0.872 AC: 3036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	- -
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	-0.81
CADD	Benign	15
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.13		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

Other links and lift over

dbSNP: rs2818940; hg19: chr9-14851617;