Genetic Variant NM_004477.3:c.671G>A (chr4-189961863-G-A) – 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_004477.3(FRG1):c.671G>A(p.Ser224Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,444,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

FRG1
NM_004477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55

Publications

0 publications found

Variant links:

Genes affected

FRG1 (HGNC:3954): (FSHD region gene 1) This gene maps to a location 100 kb centromeric of the repeat units on chromosome 4q35 which are deleted in facioscapulohumeral muscular dystrophy (FSHD). It is evolutionarily conserved and has related sequences on multiple human chromosomes but DNA sequence analysis did not reveal any homology to known genes. In vivo studies demonstrate the encoded protein is localized to the nucleolus. [provided by RefSeq, Jul 2008]

FRG1 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=0.10877496).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004477.3. 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
	FRG1	NM_004477.3	MANE Select	c.671G>A	p.Ser224Asn	missense	Exon 8 of 9	NP_004468.1	Q14331

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRG1	ENST00000226798.9	TSL:1 MANE Select	c.671G>A	p.Ser224Asn	missense	Exon 8 of 9	ENSP00000226798.4	Q14331
FRG1	ENST00000896233.1		c.686G>A	p.Ser229Asn	missense	Exon 8 of 9	ENSP00000566292.1
FRG1	ENST00000940554.1		c.671G>A	p.Ser224Asn	missense	Exon 8 of 9	ENSP00000610613.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000419

AC:

AN:

238584

AF XY:

0.00000771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000570

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1444166

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32712

American (AMR)

AF:

0.00

AC:

AN:

42302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39208

South Asian (SAS)

AF:

0.00

AC:

AN:

82304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103340

Other (OTH)

AF:

0.00

AC:

AN:

59718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.054

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.82

M_CAP

Benign

0.0065

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

PhyloP100

5.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.11

REVEL

Benign

0.083

Sift

Benign

0.74

Sift4G

Benign

0.66

Polyphen

0.028

Vest4

0.26

MutPred

0.33

Loss of phosphorylation at S224 (P = 0.0208)

MVP

0.35

MPC

0.30

ClinPred

0.069

GERP RS

3.0

Varity_R

0.31

gMVP

0.047

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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