Genetic Variant GMFB:p.Arg135His (chr14-54478113-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004124.3(GMFB):c.404G>A(p.Arg135His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000584 in 1,455,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 2 hom. )

Consequence

GMFB
NM_004124.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

Publications

0 publications found

Variant links:

Genes affected

GMFB (HGNC:4373): (glia maturation factor beta) Predicted to enable Arp2/3 complex binding activity. Predicted to be involved in actin filament debranching and negative regulation of Arp2/3 complex-mediated actin nucleation. Predicted to act upstream of or within learning and locomotory behavior. [provided by Alliance of Genome Resources, Apr 2022]

GMFB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053112477).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004124.3. 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
	GMFB	NM_004124.3	MANE Select	c.404G>A	p.Arg135His	missense	Exon 7 of 7	NP_004115.1	P60983

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GMFB	ENST00000358056.8	TSL:1 MANE Select	c.404G>A	p.Arg135His	missense	Exon 7 of 7	ENSP00000350757.3	P60983
GMFB	ENST00000553333.1	TSL:3	c.443G>A	p.Arg148His	missense	Exon 8 of 8	ENSP00000451920.1	G3V4P8
GMFB	ENST00000554908.5	TSL:1	c.*2877G>A		3_prime_UTR	Exon 4 of 4	ENSP00000452410.1	G3V3X4

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000122

AC:

AN:

180412

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000737

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000621

AC:

AN:

1304374

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

649520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28416

American (AMR)

AF:

0.00

AC:

AN:

30146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23084

East Asian (EAS)

AF:

0.000244

AC:

AN:

36940

South Asian (SAS)

AF:

0.00102

AC:

AN:

68656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50356

Middle Eastern (MID)

AF:

0.000191

AC:

AN:

5232

European-Non Finnish (NFE)

AF:

9.93e-7

AC:

AN:

1007466

Other (OTH)

AF:

0.00

AC:

AN:

54078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

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

AF:

0.0000265

AC:

AN:

151008

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41124

American (AMR)

AF:

0.00

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000388

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67778

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.0000227

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.000579

AC:

AN:

3470

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

Benign

0.097

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

0.069

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

M_CAP

Benign

0.0084

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

2.7

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

REVEL

Benign

0.076

Sift

Benign

0.040

Sift4G

Benign

0.12

Polyphen

0.15

Vest4

0.17

MVP

0.44

MPC

0.64

ClinPred

0.081

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.31

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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