Genetic Variant GMFG:p.Arg40Gln (chr19-39335292-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004877.4(GMFG):c.119G>A(p.Arg40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,565,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40G) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GMFG
NM_004877.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

GMFG (HGNC:4374): (glia maturation factor gamma) 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 be located in extracellular region; ficolin-1-rich granule lumen; and secretory granule lumen. [provided by Alliance of Genome Resources, Apr 2022]

GMFG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23385805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMFG	NM_004877.4 link	c.119G>A	p.Arg40Gln	missense_variant	Exon 3 of 7	ENST00000597595.6	NP_004868.1	O60234
GMFG	NM_001411106.1 link	c.20G>A	p.Arg7Gln	missense_variant	Exon 3 of 7		NP_001398035.1
GMFG	NM_001301008.2 link	c.-5G>A		5_prime_UTR_variant	Exon 2 of 6		NP_001287937.1	O60234M0R1D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMFG	ENST00000597595.6 link	c.119G>A	p.Arg40Gln	missense_variant	Exon 3 of 7	1	NM_004877.4	ENSP00000472249.1		O60234

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000189

AC:

AN:

211998

Hom.:

AF XY:

0.00000894

AC XY:

AN XY:

111904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000311

Gnomad OTH exome

AF:

0.000198

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1413620

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

697086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000447

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.0000343

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>A (p.R40Q) alteration is located in exon 3 (coding exon 3) of the GMFG gene. This alteration results from a G to A substitution at nucleotide position 119, causing the arginine (R) at amino acid position 40 to be replaced by a glutamine (Q). 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

Benign

0.071

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;.;T;T;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.97

D;D;.;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;.;.;.;.;.

PrimateAI

Benign

0.44

REVEL

Benign

0.15

Sift4G

Benign

0.18

T;T;.;.;T;T

Polyphen

0.76

P;.;.;.;.;.

Vest4

0.33

MutPred

0.36

Loss of ubiquitination at K38 (P = 0.0806);Loss of ubiquitination at K38 (P = 0.0806);.;.;Loss of ubiquitination at K38 (P = 0.0806);Loss of ubiquitination at K38 (P = 0.0806);

MVP

0.61

MPC

0.29

ClinPred

0.57

GERP RS

4.8

Varity_R

0.57

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over