19-39329600-A-C

Variant names:

• chr19-39329600-A-C
• rs770900962
• NM_004877.4:c.227T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004877.4(GMFG):​c.227T>G​(p.Val76Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GMFG NM_004877.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.233

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]

ACMG classification

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=0.17350131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMFG	NM_004877.4	c.227T>G	p.Val76Gly	missense_variant	Exon 5 of 7	ENST00000597595.6	NP_004868.1
GMFG	NM_001411106.1	c.128T>G	p.Val43Gly	missense_variant	Exon 5 of 7		NP_001398035.1
GMFG	NM_001301008.2	c.104T>G	p.Val35Gly	missense_variant	Exon 4 of 6		NP_001287937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMFG	ENST00000597595.6	c.227T>G	p.Val76Gly	missense_variant	Exon 5 of 7	1	NM_004877.4	ENSP00000472249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250452 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135486

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458884 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725952

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227T>G (p.V76G) alteration is located in exon 5 (coding exon 5) of the GMFG gene. This alteration results from a T to G substitution at nucleotide position 227, causing the valine (V) at amino acid position 76 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.067	T;T;.;T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.42	T;T;T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.1	.;.;.;.;.;D
REVEL	Benign	0.034
Sift	Pathogenic	0.0	.;.;.;.;.;D
Sift4G	Benign	0.37	T;T;T;.;T;.
Polyphen		0.047	.;B;.;.;.;.
Vest4		0.27
MutPred		0.36		.;Loss of stability (P = 0.0049);Loss of stability (P = 0.0049);.;.;.;
MVP		0.33
MPC		0.23
ClinPred		0.29	T
GERP RS		3.1
Varity_R		0.34
gMVP		0.50

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

Other links and lift over

dbSNP: rs770900962; hg19: chr19-39820240;