Variant 9-14737577-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001379081.2(FREM1):c.6359A>T(p.His2120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2120R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FREM1
NM_001379081.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.582

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.072227746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2 linkuse as main transcript	c.6359A>T	p.His2120Leu	missense_variant	37/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4 linkuse as main transcript	c.6359A>T	p.His2120Leu	missense_variant	37/37	5	NM_001379081.2	P1	Q5H8C1-1
FREM1	ENST00000380894.5 linkuse as main transcript	c.1967A>T	p.His656Leu	missense_variant	14/14	1			Q5H8C1-2
FREM1	ENST00000380875.7 linkuse as main transcript	c.*925A>T		3_prime_UTR_variant, NMD_transcript_variant	31/31	1
FREM1	ENST00000427623.5 linkuse as main transcript	c.*540A>T		3_prime_UTR_variant, NMD_transcript_variant	11/11	5			Q5H8C1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000968

AC:

AN:

206632

Hom.:

AF XY:

0.00

AC XY:

AN XY:

111542

show subpopulations

Gnomad AFR exome

AF:

0.0000735

Gnomad AMR exome

AF:

0.0000377

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000140

AC:

AN:

1428366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.0000262

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.6359A>T (p.H2120L) alteration is located in exon 38 (coding exon 36) of the FREM1 gene. This alteration results from a A to T substitution at nucleotide position 6359, causing the histidine (H) at amino acid position 2120 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.0010

DANN

Benign

0.56

DEOGEN2

Benign

0.068

T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.55

T;T;.

M_CAP

Benign

0.0074

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.18

MutPred

0.41

Gain of stability (P = 0.0712);.;Gain of stability (P = 0.0712);

MVP

0.048

ClinPred

0.029

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.56

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over