rs10810249

chr9-14806850-C-Achr9-14806850-C-T

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.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:7
• Conservation: PhyloP100: -0.641

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]

ACMG classification

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	UniProt
FREM1	NM_001379081.2	c.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001379081.2	P1
FREM1	ENST00000380875.7	c.3089-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29248 AN: 151998 Hom.: 3329 Cov.: 32

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

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.: 24 AF XY: 0.230 AC XY: 161039 AN XY: 701640

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.: 32 AF XY: 0.192 AC XY: 14278 AN XY: 74356

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:7

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	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: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. -

not provided Benign:2

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

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

Other links and lift over

dbSNP: rs10810249; hg19: chr9-14806848; COSMIC: COSV66524500;