chr16-74457901-C-T

Variant names:

• chr16-74457901-C-T
• rs1432226434
• NM_001145667.2:c.3238G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145667.2(GLG1):​c.3238G>A​(p.Ala1080Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GLG1 NM_001145667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42228127).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145667.2. 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
	GLG1	NM_001145667.2	MANE Select	c.3238G>A	p.Ala1080Thr	missense	Exon 24 of 26	NP_001139139.1	Q92896-1
	GLG1	NM_012201.6		c.3238G>A	p.Ala1080Thr	missense	Exon 24 of 27	NP_036333.2	Q92896-2
	GLG1	NM_001145666.2		c.3205G>A	p.Ala1069Thr	missense	Exon 23 of 26	NP_001139138.1	Q92896-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLG1	ENST00000422840.7	TSL:1 MANE Select	c.3238G>A	p.Ala1080Thr	missense	Exon 24 of 26	ENSP00000405984.3	Q92896-1
	GLG1	ENST00000205061.9	TSL:1	c.3238G>A	p.Ala1080Thr	missense	Exon 24 of 27	ENSP00000205061.5	Q92896-2
	GLG1	ENST00000567951.5	TSL:1	n.*1317G>A		non_coding_transcript_exon	Exon 19 of 21	ENSP00000455950.1	H3BQU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461664 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

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	0.33
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.50
MutPred		0.57		Loss of helix (P = 0.0558)
MVP		0.28
MPC		0.53
ClinPred		0.77	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.61
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs1432226434; hg19: chr16-74491799; COSMIC: COSV105857237; COSMIC: COSV105857237;