Variant 4-143585880-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001168235.2(FREM3):c.6142G>A(p.Val2048Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,537,254 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 32 hom. )

Consequence

FREM3
NM_001168235.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.47

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:

ENSG00000251600 (HGNC:):

ENSG00000251600 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003987968).

BP6

Variant 4-143585880-C-T is Benign according to our data. Variant chr4-143585880-C-T is described in ClinVar as [Benign]. Clinvar id is 780493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1960/152256) while in subpopulation AFR AF= 0.0447 (1857/41526). AF 95% confidence interval is 0.043. There are 41 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM3	NM_001168235.2 linkuse as main transcript	c.6142G>A	p.Val2048Met	missense_variant	7/8	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.6142G>A	p.Val2048Met	missense_variant	7/8	5	NM_001168235.2	ENSP00000332886.5	P0C091
ENSG00000251600	ENST00000511042.5 linkuse as main transcript	n.191+13299C>T		intron_variant		5
ENSG00000251600	ENST00000641328.1 linkuse as main transcript	n.861+13299C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1955

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0447

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00299

AC:

431

AN:

144232

Hom.:

AF XY:

0.00225

AC XY:

173

AN XY:

76934

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00138

GnomAD4 exome

AF:

0.00130

AC:

1794

AN:

1384998

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

755

AN XY:

683424

show subpopulations

Gnomad4 AFR exome

AF:

0.0457

Gnomad4 AMR exome

AF:

0.00263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000353

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000501

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.0129

AC:

1960

AN:

152256

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0447

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.0143

ESP6500AA

AF:

0.0419

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.00483

AC:

127

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.13

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Vest4

0.30

MVP

0.30

ClinPred

0.083

GERP RS

0.46

Varity_R

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over