22-31400626-C-G

Variant names:

• chr22-31400626-C-G
• rs1229776376
• NM_004147.4:c.49C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004147.4(DRG1):​c.49C>G​(p.Arg17Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DRG1 NM_004147.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

Genes affected

DRG1 (HGNC:3029): (developmentally regulated GTP binding protein 1) Enables several functions, including GTPase activity; identical protein binding activity; and potassium ion binding activity. Involved in positive regulation of microtubule polymerization and regulation of mitotic spindle assembly. Located in cytosol and nuclear body. Part of polysome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRG1	NM_004147.4	c.49C>G	p.Arg17Gly	missense_variant	Exon 2 of 9	ENST00000331457.9	NP_004138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRG1	ENST00000331457.9	c.49C>G	p.Arg17Gly	missense_variant	Exon 2 of 9	1	NM_004147.4	ENSP00000329715.4
DRG1	ENST00000416465.5	n.49C>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000408091.1
DRG1	ENST00000433341.5	n.116C>G		non_coding_transcript_exon_variant	Exon 2 of 7	3
DRG1	ENST00000486584.1	n.93+901C>G		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460516 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726576

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: 0.00

Gnomad4 OTH exome AF: 0.0000332

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 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>G (p.R17G) alteration is located in exon 2 (coding exon 2) of the DRG1 gene. This alteration results from a C to G substitution at nucleotide position 49, causing the arginine (R) at amino acid position 17 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.72
MutPred		0.52		Loss of MoRF binding (P = 0.008);
MVP		0.85
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.90

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: rs1229776376; hg19: chr22-31796612;