9-14737544-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001379081.2(FREM1):c.6392C>T(p.Pro2131Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,608,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
FREM1
NM_001379081.2 missense
NM_001379081.2 missense
Scores
2
3
14
Clinical Significance
Conservation
PhyloP100: 4.77
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 Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FREM1 | NM_001379081.2 | c.6392C>T | p.Pro2131Leu | missense_variant | 37/37 | ENST00000380880.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FREM1 | ENST00000380880.4 | c.6392C>T | p.Pro2131Leu | missense_variant | 37/37 | 5 | NM_001379081.2 | P1 | |
FREM1 | ENST00000380894.5 | c.2000C>T | p.Pro667Leu | missense_variant | 14/14 | 1 | |||
FREM1 | ENST00000380875.7 | c.*958C>T | 3_prime_UTR_variant, NMD_transcript_variant | 31/31 | 1 | ||||
FREM1 | ENST00000427623.5 | c.*573C>T | 3_prime_UTR_variant, NMD_transcript_variant | 11/11 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000250 AC: 6AN: 239914Hom.: 0 AF XY: 0.0000307 AC XY: 4AN XY: 130190
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GnomAD4 exome AF: 0.0000261 AC: 38AN: 1456412Hom.: 0 Cov.: 35 AF XY: 0.0000290 AC XY: 21AN XY: 724140
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | The c.6392C>T (p.P2131L) alteration is located in exon 38 (coding exon 36) of the FREM1 gene. This alteration results from a C to T substitution at nucleotide position 6392, causing the proline (P) at amino acid position 2131 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FREM1-related conditions. This variant is present in population databases (rs764505995, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2131 of the FREM1 protein (p.Pro2131Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;T;.
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;B
Vest4
MutPred
Gain of stability (P = 0.0523);.;Gain of stability (P = 0.0523);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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