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GeneBe

9-14775855-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379081.2(FREM1):c.4791T>C(p.Asp1597=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,082 control chromosomes in the GnomAD database, including 615,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 55966 hom., cov: 32)
Exomes 𝑓: 0.88 ( 559915 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0120
Variant links:
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 Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 9-14775855-A-G is Benign according to our data. Variant chr9-14775855-A-G is described in ClinVar as [Benign]. Clinvar id is 262542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14775855-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.012 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FREM1NM_001379081.2 linkuse as main transcriptc.4791T>C p.Asp1597= synonymous_variant 25/37 ENST00000380880.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FREM1ENST00000380880.4 linkuse as main transcriptc.4791T>C p.Asp1597= synonymous_variant 25/375 NM_001379081.2 P1Q5H8C1-1

Frequencies

GnomAD3 genomes
AF:
0.857
AC:
130176
AN:
151914
Hom.:
55942
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.795
Gnomad AMI
AF:
0.683
Gnomad AMR
AF:
0.875
Gnomad ASJ
AF:
0.893
Gnomad EAS
AF:
0.858
Gnomad SAS
AF:
0.857
Gnomad FIN
AF:
0.910
Gnomad MID
AF:
0.883
Gnomad NFE
AF:
0.882
Gnomad OTH
AF:
0.872
GnomAD3 exomes
AF:
0.870
AC:
216627
AN:
249084
Hom.:
94283
AF XY:
0.872
AC XY:
117889
AN XY:
135126
show subpopulations
Gnomad AFR exome
AF:
0.796
Gnomad AMR exome
AF:
0.834
Gnomad ASJ exome
AF:
0.897
Gnomad EAS exome
AF:
0.870
Gnomad SAS exome
AF:
0.866
Gnomad FIN exome
AF:
0.910
Gnomad NFE exome
AF:
0.881
Gnomad OTH exome
AF:
0.869
GnomAD4 exome
AF:
0.875
AC:
1278506
AN:
1461050
Hom.:
559915
Cov.:
55
AF XY:
0.876
AC XY:
636352
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.799
Gnomad4 AMR exome
AF:
0.838
Gnomad4 ASJ exome
AF:
0.894
Gnomad4 EAS exome
AF:
0.842
Gnomad4 SAS exome
AF:
0.867
Gnomad4 FIN exome
AF:
0.907
Gnomad4 NFE exome
AF:
0.879
Gnomad4 OTH exome
AF:
0.871
GnomAD4 genome
AF:
0.857
AC:
130253
AN:
152032
Hom.:
55966
Cov.:
32
AF XY:
0.858
AC XY:
63786
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.795
Gnomad4 AMR
AF:
0.875
Gnomad4 ASJ
AF:
0.893
Gnomad4 EAS
AF:
0.857
Gnomad4 SAS
AF:
0.857
Gnomad4 FIN
AF:
0.910
Gnomad4 NFE
AF:
0.882
Gnomad4 OTH
AF:
0.866
Alfa
AF:
0.879
Hom.:
82734
Bravo
AF:
0.851
Asia WGS
AF:
0.803
AC:
2793
AN:
3478
EpiCase
AF:
0.879
EpiControl
AF:
0.882

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Oculotrichoanal syndrome Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxApr 28, 2020- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
Cadd
Benign
1.8
Dann
Benign
0.34
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1032474; hg19: chr9-14775853; API