10-102260051-A-C

Variant names:

• chr10-102260051-A-C
• rs777289121
• NM_001377137.1:c.98A>C

Variant summary

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

The NM_001377137.1(GBF1):​c.98A>C​(p.Asp33Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GBF1 NM_001377137.1 missense, splice_region
• Scores: Splicing: ADA: 0.8189
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.26

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]

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
GBF1	NM_001377137.1	c.98A>C	p.Asp33Ala	missense_variant, splice_region_variant	Exon 3 of 40	ENST00000369983.5	NP_001364066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBF1	ENST00000369983.5	c.98A>C	p.Asp33Ala	missense_variant, splice_region_variant	Exon 3 of 40	1	NM_001377137.1	ENSP00000359000.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98A>C (p.D33A) alteration is located in exon 3 (coding exon 2) of the GBF1 gene. This alteration results from a A to C substitution at nucleotide position 98, causing the aspartic acid (D) at amino acid position 33 to be replaced by an alanine (A). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Sift4G	Benign	0.12	T
Polyphen		0.80	P
Vest4		0.87
MutPred		0.11		Loss of disorder (P = 0.0896);
MVP		0.57
MPC		0.79
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Pathogenic	0.87
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: rs777289121; hg19: chr10-104019808;