rs281875281
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_001379081.2(FREM1):āc.3971T>Gā(p.Leu1324Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,596,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.00014 ( 0 hom., cov: 32)
Exomes š: 0.00023 ( 0 hom. )
Consequence
FREM1
NM_001379081.2 missense
NM_001379081.2 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 8.50
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
Variant 9-14792753-A-C is Pathogenic according to our data. Variant chr9-14792753-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14792753-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FREM1 | NM_001379081.2 | c.3971T>G | p.Leu1324Arg | missense_variant | 22/37 | ENST00000380880.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FREM1 | ENST00000380880.4 | c.3971T>G | p.Leu1324Arg | missense_variant | 22/37 | 5 | NM_001379081.2 | P1 | |
FREM1 | ENST00000380875.7 | c.3971T>G | p.Leu1324Arg | missense_variant, NMD_transcript_variant | 23/31 | 1 | |||
FREM1 | ENST00000466679.1 | n.49T>G | non_coding_transcript_exon_variant | 1/4 | 3 | ||||
FREM1 | ENST00000497634.2 | n.132T>G | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000133 AC: 31AN: 232776Hom.: 0 AF XY: 0.000119 AC XY: 15AN XY: 125904
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GnomAD4 exome AF: 0.000226 AC: 327AN: 1444134Hom.: 0 Cov.: 29 AF XY: 0.000198 AC XY: 142AN XY: 716874
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74362
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1324 of the FREM1 protein (p.Leu1324Arg). This variant is present in population databases (rs281875281, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive Manitoba oculo-tricho-anal (MOTA) syndrome (PMID: 21507892, 23112756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FREM1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Oculotrichoanal syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.3971T>G (p.Leu1324Arg) variant has been reported in two studies in which it was identified in a compound heterozygous state in two patients with Manitoba oculotrichoanal syndrome (Slavotinek et al. 2011; Mitter et al. 2012). Trio analysis in both studies confirmed the zygosity of the patients and identified the variant in a heterozygous state in the unaffected parents of both patients. The p.Leu1324Arg variant was absent from 252 control alleles but is reported at a frequency of 0.00023 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Leu1324Arg variant is classified as likely pathogenic for Manitoba oculotrichoanal syndrome. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at