18-11689714-A-G

Variant names:

• chr18-11689714-A-G
• rs2031172955
• NM_182978.4:c.151A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182978.4(GNAL):​c.151A>G​(p.Thr51Ala) 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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T51P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAL NM_182978.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.125
• Publications: 0 publications found

Genes affected

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL Gene-Disease associations (from GenCC):

• dystonia 25

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24867496).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182978.4. 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
	GNAL	NM_182978.4	MANE Select	c.151A>G	p.Thr51Ala	missense	Exon 1 of 12	NP_892023.1	P38405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.151A>G	p.Thr51Ala	missense	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.25A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1344050 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 662818

African (AFR) AF: 0.00 AC: 0 AN: 27260

American (AMR) AF: 0.00 AC: 0 AN: 30764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23828

East Asian (EAS) AF: 0.00 AC: 0 AN: 29746

South Asian (SAS) AF: 0.00 AC: 0 AN: 75420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1059928

Other (OTH) AF: 0.00 AC: 0 AN: 56048

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.3
DANN	Benign	0.79
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.54	T
PhyloP100		0.13
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Benign	0.80	T
Vest4		0.022
MutPred		0.19		Gain of helix (P = 0.027)
MVP		0.47
MPC		1.5
ClinPred		0.72	D
GERP RS		-0.78
PromoterAI		0.17	Neutral
gMVP		0.22
Mutation Taster		=89/11	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2031172955; hg19: chr18-11689713;