19-3151717-C-A

Variant names:

• chr19-3151717-C-A
• rs1914885378
• NM_002068.4:c.496C>A

Variant summary

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

The NM_002068.4(GNA15):​c.496C>A​(p.His166Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. H166Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GNA15 NM_002068.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.730
• Publications: 0 publications found

Genes affected

GNA15 (HGNC:4383): (G protein subunit alpha 15) Enables G protein-coupled receptor binding activity. Involved in positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway. Predicted to be located in plasma membrane. Predicted to be part of heterotrimeric G-protein complex. [provided by Alliance of Genome Resources, Apr 2022]

GNA15-DT (HGNC:55293): (GNA15 divergent transcript)

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=0.12634939).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002068.4. 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
	GNA15	NM_002068.4	MANE Select	c.496C>A	p.His166Asn	missense	Exon 4 of 7	NP_002059.3	P30679
	GNA15-DT	NR_110670.1		n.159-1927G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNA15	ENST00000262958.4	TSL:1 MANE Select	c.496C>A	p.His166Asn	missense	Exon 4 of 7	ENSP00000262958.2	P30679
	GNA15	ENST00000586082.1	TSL:3	n.457C>A		non_coding_transcript_exon	Exon 2 of 3
	GNA15	ENST00000592455.1	TSL:3	n.*526C>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000467256.1	K7EP74

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449122 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 720796

African (AFR) AF: 0.00 AC: 0 AN: 32992

American (AMR) AF: 0.00 AC: 0 AN: 42704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.00 AC: 0 AN: 84840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1106384

Other (OTH) AF: 0.00 AC: 0 AN: 59836

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.85
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.71	T
PhyloP100		0.73
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.25
Sift	Benign	0.37	T
Sift4G	Benign	0.81	T
Vest4		0.23
MutPred		0.54		Loss of catalytic residue at E168 (P = 0.1156)
MVP		0.73
MPC		0.63
ClinPred		0.20	T
GERP RS		0.85
gMVP		0.52
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1914885378; hg19: chr19-3151715; COSMIC: COSV99505210;