rs281875281

chr9-14792753-A-Cchr9-14792753-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001379081.2(FREM1):c.3971T>G(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:2 O:1
• 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]

ACMG classification

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: 21 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 31 AN: 232776 Hom.: 0 AF XY: 0.000119 AC XY: 15 AN XY: 125904

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000226 AC: 327 AN: 1444134 Hom.: 0 Cov.: 29 AF XY: 0.000198 AC XY: 142 AN XY: 716874

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Other:1

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. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
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	-	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.86
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95

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

Other links and lift over

dbSNP: rs281875281; hg19: chr9-14792751;