chr10-102352496-A-G

Variant names:

• chr10-102352496-A-G
• rs1467300528
• NM_001377137.1:c.562A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001377137.1(GBF1):​c.562A>G​(p.Met188Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GBF1 NM_001377137.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.26
• 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• BS2: High AC in GnomAdExome4 at 9 AD gene.

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.562A>G	p.Met188Val	missense	Exon 7 of 40	NP_001364066.1	Q92538-4
	GBF1	NM_001411027.1		c.562A>G	p.Met188Val	missense	Exon 7 of 41	NP_001397956.1	A0A669KBG8
	GBF1	NM_001391922.1		c.562A>G	p.Met188Val	missense	Exon 7 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.562A>G	p.Met188Val	missense	Exon 7 of 40	ENSP00000359000.4	Q92538-4
	GBF1	ENST00000673650.1		c.562A>G	p.Met188Val	missense	Exon 7 of 41	ENSP00000501233.1	A0A669KBG8
	GBF1	ENST00000674034.1		c.562A>G	p.Met188Val	missense	Exon 7 of 41	ENSP00000501064.1	A0A669KB10

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459820 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726318

African (AFR) AF: 0.0000897 AC: 3 AN: 33446

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110144

Other (OTH) AF: 0.0000994 AC: 6 AN: 60332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth Disease, axonal, type 2GG (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.11	T
Polyphen		0.48	P
Vest4		0.94
MutPred		0.59		Loss of phosphorylation at T184 (P = 0.3045)
MVP		0.66
MPC		0.48
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.47
gMVP		0.86
Mutation Taster		=32/68	disease causing

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: rs1467300528; hg19: chr10-104112253; COSMIC: COSV64147687;