Genetic Variant GMFB:p.Gly106Arg (chr14-54479827-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004124.3(GMFB):c.316G>A(p.Gly106Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GMFB
NM_004124.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.36

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMFB	NM_004124.3 link	c.316G>A	p.Gly106Arg	missense_variant	Exon 6 of 7	ENST00000358056.8	NP_004115.1	P60983

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GMFB	ENST00000358056.8 link	c.316G>A	p.Gly106Arg	missense_variant	Exon 6 of 7	1	NM_004124.3	ENSP00000350757.3	P60983
GMFB	ENST00000553333.1 link	c.355G>A	p.Gly119Arg	missense_variant	Exon 7 of 8	3		ENSP00000451920.1	G3V4P8
GMFB	ENST00000554908.5 link	c.*1163G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000452410.1	G3V3X4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453332

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723546

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.316G>A (p.G106R) alteration is located in exon 6 (coding exon 6) of the GMFB gene. This alteration results from a G to A substitution at nucleotide position 316, causing the glycine (G) at amino acid position 106 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.8

D;.;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

D;.;D

Sift4G

Benign

0.076

T;T;T

Polyphen

0.65

P;P;.

Vest4

0.91

MutPred

0.83

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);.;

MVP

0.63

MPC

1.4

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 32

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over