19-3151816-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002068.4(GNA15):c.595G>A(p.Val199Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,611,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: GNA15 NM_002068.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10349566).
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNA15	NM_002068.4	c.595G>A	p.Val199Met	missense_variant	4/7	ENST00000262958.4
GNA15-DT	NR_110670.1	n.159-2026C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNA15	ENST00000262958.4	c.595G>A	p.Val199Met	missense_variant	4/7	1	NM_002068.4	P1
GNA15-DT	ENST00000587587.1	n.159-2026C>T		intron_variant, non_coding_transcript_variant		2
GNA15	ENST00000586082.1	n.556G>A		non_coding_transcript_exon_variant	2/3	3
GNA15	ENST00000592455.1	c.*625G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000725 AC: 18 AN: 248374 Hom.: 1 AF XY: 0.0000669 AC XY: 9 AN XY: 134616

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1459266 Hom.: 1 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726020

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74360

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Oct 29, 2021

The c.595G>A (p.V199M) alteration is located in exon 4 (coding exon 4) of the GNA15 gene. This alteration results from a G to A substitution at nucleotide position 595, causing the valine (V) at amino acid position 199 to be replaced by a methionine (M). 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	0.30
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.36	D
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.30
Sift	Benign	0.040	D
Sift4G	Benign	0.092	T
Vest4		0.31
MVP		0.82
MPC		0.63
ClinPred		0.050	T
GERP RS		4.6
gMVP		0.60

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: rs151214875; hg19: chr19-3151814; COSMIC: COSV53585237;