Genetic Variant FRG1:p.Asp193Asn (chr4-189960787-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004477.3(FRG1):c.577G>A(p.Asp193Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,609,004 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 7 hom. )

Consequence

FRG1
NM_004477.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0083974).

BP6

Variant 4-189960787-G-A is Benign according to our data. Variant chr4-189960787-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 718404.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

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.577G>A	p.Asp193Asn	missense	Exon 7 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.577G>A	p.Asp193Asn	missense	Exon 7 of 9	ENSP00000226798.4	Q14331
FRG1	ENST00000896233.1		c.577G>A	p.Asp193Asn	missense	Exon 7 of 9	ENSP00000566292.1
FRG1	ENST00000940554.1		c.577G>A	p.Asp193Asn	missense	Exon 7 of 9	ENSP00000610613.1

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00100

AC:

197

AN:

196080

AF XY:

0.000994

show subpopulations

Gnomad AFR exome

AF:

0.0000794

Gnomad AMR exome

AF:

0.000656

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000516

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000783

AC:

1140

AN:

1456816

Hom.:

Cov.:

AF XY:

0.000786

AC XY:

570

AN XY:

724798

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33188

American (AMR)

AF:

0.000498

AC:

AN:

44168

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

499

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000607

AC:

AN:

85698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000386

AC:

429

AN:

1110680

Other (OTH)

AF:

0.00207

AC:

124

AN:

60034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000920

AC:

140

AN:

152188

Hom.:

Cov.:

AF XY:

0.000901

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41436

American (AMR)

AF:

0.00111

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68028

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00257

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00205

AC:

ExAC

AF:

0.000914

AC:

110

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.020

MetaRNN

Benign

0.0084

MetaSVM

Benign

-0.67

PhyloP100

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.22

Sift

Uncertain

0.016

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.40

MVP

0.68

MPC

0.57

ClinPred

0.15

GERP RS

4.0

Varity_R

0.54

gMVP

0.25

Mutation Taster

=86/14

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over