Variant 9-14776147-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001379081.2(FREM1):c.4499A>G(p.Glu1500Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,409,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1500V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.82

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]

FREM1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-14776147-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.32117483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM1	NM_001379081.2 link	c.4499A>G	p.Glu1500Gly	missense_variant	25/37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4 link	c.4499A>G	p.Glu1500Gly	missense_variant	25/37	5	NM_001379081.2	ENSP00000370262.3		Q5H8C1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000967

AC:

AN:

206884

Hom.:

AF XY:

0.0000181

AC XY:

AN XY:

110306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000977

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1409746

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

695032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

T;T;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.5

M;.;M

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Benign

0.13

Sift

Benign

0.087

T;D;T

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.92

P;.;P

Vest4

0.33

MutPred

0.44

Loss of stability (P = 0.0358);.;Loss of stability (P = 0.0358);

MVP

0.73

ClinPred

0.76

GERP RS

6.0

Varity_R

0.48

gMVP

0.66

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over