16-74457934-T-C

Position:

• chr16-74457934-T-C

Variant summary

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

The NM_001145667.2(GLG1):​c.3205A>G​(p.Thr1069Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLG1 NM_001145667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

GLG1 (HGNC:):

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/exons	MANE	Protein	UniProt
GLG1	NM_001145667.2	c.3205A>G	p.Thr1069Ala	missense_variant	24/26	ENST00000422840.7	NP_001139139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLG1	ENST00000422840.7	c.3205A>G	p.Thr1069Ala	missense_variant	24/26	1	NM_001145667.2	ENSP00000405984.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 26, 2024

The c.3205A>G (p.T1069A) alteration is located in exon 24 (coding exon 24) of the GLG1 gene. This alteration results from a A to G substitution at nucleotide position 3205, causing the threonine (T) at amino acid position 1069 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	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.52	T;T;T
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.72	P;P;.
Vest4		0.70
MutPred		0.64		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;
MVP		0.37
MPC		0.47
ClinPred		0.75	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs2014625213; hg19: chr16-74491832;