NM_004877.4:c.227T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17350131).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004877.4. 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
	GMFG	NM_004877.4	MANE Select	c.227T>G	p.Val76Gly	missense	Exon 5 of 7	NP_004868.1	O60234
	GMFG	NM_001411106.1		c.128T>G	p.Val43Gly	missense	Exon 5 of 7	NP_001398035.1	M0R0C1
	GMFG	NM_001301008.2		c.104T>G	p.Val35Gly	missense	Exon 4 of 6	NP_001287937.1	M0R1D2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMFG	ENST00000597595.6	TSL:1 MANE Select	c.227T>G	p.Val76Gly	missense	Exon 5 of 7	ENSP00000472249.1	O60234
	GMFG	ENST00000598034.5	TSL:1	c.227T>G	p.Val76Gly	missense	Exon 5 of 6	ENSP00000469877.1	M0QYJ8
	GMFG	ENST00000904715.1		c.227T>G	p.Val76Gly	missense	Exon 6 of 8	ENSP00000574774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250452 AF XY: 0.00000738

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109318

Other (OTH) AF: 0.00 AC: 0 AN: 60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000192981), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.23
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.37	T
Polyphen		0.047	B
Vest4		0.27
MutPred		0.36		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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs770900962; hg19: chr19-39820240;