chr16-74462533-T-G

Position:

• chr16-74462533-T-G

Variant summary

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

The NM_001145667.2(GLG1):​c.2889A>C​(p.Leu963Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: GLG1 NM_001145667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0180

Genes affected

GLG1 (HGNC:4316): (golgi glycoprotein 1) Predicted to enable fibroblast growth factor binding activity. Predicted to act upstream of or within several processes, including negative regulation of protein processing; negative regulation of transforming growth factor beta receptor signaling pathway; and regulation of chondrocyte differentiation. Located in Golgi apparatus. [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=0.17868546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLG1	NM_001145667.2	c.2889A>C	p.Leu963Phe	missense_variant	21/26	ENST00000422840.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLG1	ENST00000422840.7	c.2889A>C	p.Leu963Phe	missense_variant	21/26	1	NM_001145667.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.2889A>C (p.L963F) alteration is located in exon 21 (coding exon 21) of the GLG1 gene. This alteration results from a A to C substitution at nucleotide position 2889, causing the leucine (L) at amino acid position 963 to be replaced by a phenylalanine (F). 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	0.24
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;D;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.17
Sift	Benign	0.047	D;T;D
Sift4G	Benign	0.092	T;T;T
Polyphen		0.033	B;B;.
Vest4		0.51
MutPred		0.35		Gain of catalytic residue at L963 (P = 0.1515);Gain of catalytic residue at L963 (P = 0.1515);.;
MVP		0.27
MPC		0.56
ClinPred		0.68	D
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753037950; hg19: chr16-74496431;