10-102358641-A-G

Variant names:

• chr10-102358641-A-G
• rs1438828928
• NM_001377137.1:c.923A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001377137.1(GBF1):​c.923A>G​(p.Asp308Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,766 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: 0.0000027 (0 hom.)
• Consequence: GBF1 NM_001377137.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.86
• Publications: 0 publications found

Genes affected

GBF1 (HGNC:4181): (golgi brefeldin A resistant guanine nucleotide exchange factor 1) This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

GBF1 Gene-Disease associations (from GenCC):

• axonal neuropathy

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377137.1. 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
	GBF1	NM_001377137.1	MANE Select	c.923A>G	p.Asp308Gly	missense	Exon 10 of 40	NP_001364066.1	Q92538-4
	GBF1	NM_001411027.1		c.1022A>G	p.Asp341Gly	missense	Exon 11 of 41	NP_001397956.1	A0A669KBG8
	GBF1	NM_001391922.1		c.1022A>G	p.Asp341Gly	missense	Exon 11 of 41	NP_001378851.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBF1	ENST00000369983.5	TSL:1 MANE Select	c.923A>G	p.Asp308Gly	missense	Exon 10 of 40	ENSP00000359000.4	Q92538-4
	GBF1	ENST00000673650.1		c.1022A>G	p.Asp341Gly	missense	Exon 11 of 41	ENSP00000501233.1	A0A669KBG8
	GBF1	ENST00000674034.1		c.998A>G	p.Asp333Gly	missense	Exon 11 of 41	ENSP00000501064.1	A0A669KB10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.21
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.021	D
Sift4G	Benign	0.093	T
Polyphen		0.80	P
Vest4		0.67
MutPred		0.26		Gain of loop (P = 0.0045)
MVP		0.44
MPC		0.66
ClinPred		0.91	D
GERP RS		6.0
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.56
Mutation Taster		=51/49	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: rs1438828928; hg19: chr10-104118398;