Genetic Variant NM_001168235.2:c.5756T>A (chr4-143621060-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001168235.2(FREM3):c.5756T>A(p.Ile1919Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22958386).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168235.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM3	NM_001168235.2	MANE Select	c.5756T>A	p.Ile1919Asn	missense	Exon 5 of 8	NP_001161707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FREM3	ENST00000329798.5	TSL:5 MANE Select	c.5756T>A	p.Ile1919Asn	missense	Exon 5 of 8	ENSP00000332886.5
GUSBP5	ENST00000511042.5	TSL:5	n.192-24025A>T		intron	N/A
GUSBP5	ENST00000641328.2		n.862+48479A>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000699

AC:

AN:

143092

AF XY:

0.0000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000941

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1385088

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683460

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078900

Other (OTH)

AF:

0.00

AC:

AN:

57974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0035

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0059

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

PhyloP100

1.6

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.7

REVEL

Benign

0.095

Sift

Uncertain

0.013

Sift4G

Uncertain

0.011

Vest4

0.27

MutPred

0.48

Gain of disorder (P = 0.0399)

MVP

0.15

ClinPred

0.16

GERP RS

-4.4

Varity_R

0.18

gMVP

0.70

Mutation Taster

=77/23

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over