Genetic Variant FREM3:p.Ile1919Thr (chr4-143621060-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001168235.2(FREM3):c.5756T>C(p.Ile1919Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,537,210 control chromosomes in the GnomAD database, including 3,426 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I1919S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.090 ( 1759 hom., cov: 32)

Exomes 𝑓: 0.014 ( 1667 hom. )

Consequence

FREM3
NM_001168235.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

7 publications found

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:

GUSBP5 (HGNC:):

GUSBP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010958254).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM3	NM_001168235.2 link	c.5756T>C	p.Ile1919Thr	missense_variant	Exon 5 of 8	ENST00000329798.5	NP_001161707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM3	ENST00000329798.5 link	c.5756T>C	p.Ile1919Thr	missense_variant	Exon 5 of 8	5	NM_001168235.2	ENSP00000332886.5		P0C091

Frequencies

GnomAD3 genomes

AF:

0.0892

AC:

13566

AN:

152058

Hom.:

1744

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0397

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0606

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.0689

GnomAD2 exomes

AF:

0.0285

AC:

4084

AN:

143092

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.0560

Gnomad FIN exome

AF:

0.000429

Gnomad NFE exome

AF:

0.00535

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0138

AC:

19113

AN:

1385034

Hom.:

1667

Cov.:

AF XY:

0.0128

AC XY:

8776

AN XY:

683432

show subpopulations

African (AFR)

AF:

0.307

AC:

9693

AN:

31562

American (AMR)

AF:

0.0225

AC:

803

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

354

AN:

25182

East Asian (EAS)

AF:

0.0382

AC:

1366

AN:

35732

South Asian (SAS)

AF:

0.00687

AC:

544

AN:

79234

European-Finnish (FIN)

AF:

0.000684

AC:

AN:

35076

Middle Eastern (MID)

AF:

0.0432

AC:

246

AN:

5696

European-Non Finnish (NFE)

AF:

0.00391

AC:

4222

AN:

1078884

Other (OTH)

AF:

0.0321

AC:

1861

AN:

57968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

779

1559

2338

3118

3897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0896

AC:

13631

AN:

152176

Hom.:

1759

Cov.:

AF XY:

0.0878

AC XY:

6534

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.293

AC:

12138

AN:

41456

American (AMR)

AF:

0.0396

AC:

606

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.0602

AC:

312

AN:

5182

South Asian (SAS)

AF:

0.00932

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00460

AC:

313

AN:

68004

Other (OTH)

AF:

0.0682

AC:

144

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

511

1022

1534

2045

2556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0357

Hom.:

1884

Bravo

AF:

0.102

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.278

AC:

385

ESP6500EA

AF:

0.00503

AC:

ExAC

AF:

0.0340

AC:

805

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.9

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.67

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.92

PhyloP100

1.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.030

REVEL

Benign

0.13

Sift

Benign

0.57

Sift4G

Benign

0.46

Vest4

0.017

ClinPred

0.0041

GERP RS

-4.4

Varity_R

0.045

gMVP

0.49

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over