14-54480882-C-A

Variant names:

• chr14-54480882-C-A
• NM_004124.3:c.275G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004124.3(GMFB):​c.275G>T​(p.Ser92Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,332,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: GMFB NM_004124.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMFB	NM_004124.3	c.275G>T	p.Ser92Ile	missense_variant	Exon 5 of 7	ENST00000358056.8	NP_004115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMFB	ENST00000358056.8	c.275G>T	p.Ser92Ile	missense_variant	Exon 5 of 7	1	NM_004124.3	ENSP00000350757.3
GMFB	ENST00000553333.1	c.314G>T	p.Ser105Ile	missense_variant	Exon 6 of 8	3		ENSP00000451920.1
GMFB	ENST00000554908.5	c.*108G>T		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000452410.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1332266 Hom.: 0 Cov.: 20 AF XY: 0.00000149 AC XY: 1 AN XY: 669086

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: 9.97e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000184 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275G>T (p.S92I) alteration is located in exon 5 (coding exon 5) of the GMFB gene. This alteration results from a G to T substitution at nucleotide position 275, causing the serine (S) at amino acid position 92 to be replaced by an isoleucine (I). 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	0.94
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;.;D
Sift4G	Benign	0.072	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.54		Gain of catalytic residue at S91 (P = 0);Gain of catalytic residue at S91 (P = 0);.;
MVP		0.67
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-54947600;