Variant 4-143621043-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001168235.2(FREM3):c.5773C>T(p.Arg1925Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000703 in 1,537,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FREM3
NM_001168235.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13

Variant links:

Genes affected

FREM3 (HGNC:25172): (FRAS1 related extracellular matrix 3) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The protein belongs to the family of FRAS1/FREM extracellular matrix proteins and may play a role cell adhesion. [provided by RefSeq, Feb 2017]

FREM3 links:

FREM3 (HGNC:):

FREM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03327486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM3	NM_001168235.2 linkuse as main transcript	c.5773C>T	p.Arg1925Cys	missense_variant	5/8	ENST00000329798.5	NP_001161707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FREM3	ENST00000329798.5 linkuse as main transcript	c.5773C>T	p.Arg1925Cys	missense_variant	5/8	5	NM_001168235.2	ENSP00000332886.5	P0C091
FREM3	ENST00000508899.1 linkuse as main transcript	n.10C>T		non_coding_transcript_exon_variant	1/3	5
ENSG00000251600	ENST00000511042.5 linkuse as main transcript	n.192-24042G>A		intron_variant		5
ENSG00000251600	ENST00000641328.1 linkuse as main transcript	n.861+48462G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000126

AC:

AN:

143170

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

76340

show subpopulations

Gnomad AFR exome

AF:

0.000764

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000753

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000521

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000469

AC:

AN:

1385068

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

683442

show subpopulations

Gnomad4 AFR exome

AF:

0.000348

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000196

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000282

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000264

ExAC

AF:

0.000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.5773C>T (p.R1925C) alteration is located in exon 5 (coding exon 5) of the FREM3 gene. This alteration results from a C to T substitution at nucleotide position 5773, causing the arginine (R) at amino acid position 1925 to be replaced by a cysteine (C). 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

0.092

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

Eigen

Benign

0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.46

M_CAP

Benign

0.029

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.16

Sift

Benign

0.069

Sift4G

Uncertain

0.0070

Vest4

0.089

MutPred

0.55

Loss of disorder (P = 0.0556);

MVP

0.46

ClinPred

0.13

GERP RS

3.3

Varity_R

0.098

gMVP

0.52

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