rs4900

chr19-3119241-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002067.5(GNA11):c.771C>T(p.Thr257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,612,358 control chromosomes in the GnomAD database, including 172,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12144 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160274 hom.)
• Consequence: GNA11 NM_002067.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.579

Genes affected

GNA11 (HGNC:4379): (G protein subunit alpha 11) The protein encoded by this gene belongs to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes one of the alpha subunits (subunit alpha-11). Mutations in this gene have been associated with hypocalciuric hypercalcemia type II (HHC2) and hypocalcemia dominant 2 (HYPOC2). Patients with HHC2 and HYPOC2 exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. [provided by RefSeq, Dec 2013]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 19-3119241-C-T is Benign according to our data. Variant chr19-3119241-C-T is described in ClinVar as [Benign]. Clinvar id is 258548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-3119241-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.579 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNA11	NM_002067.5	c.771C>T	p.Thr257=	synonymous_variant	6/7	ENST00000078429.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNA11	ENST00000078429.9	c.771C>T	p.Thr257=	synonymous_variant	6/7	1	NM_002067.5	P1
	ENST00000587701.1	n.51+13G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58250 AN: 151846 Hom.: 12137 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.395

GnomAD3 exomes AF: 0.427 AC: 107299 AN: 251156 Hom.: 23629 AF XY: 0.431 AC XY: 58477 AN XY: 135738

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.407

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.436

GnomAD4 exome AF: 0.465 AC: 679315 AN: 1460394 Hom.: 160274 Cov.: 42 AF XY: 0.465 AC XY: 337506 AN XY: 726498

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.422

Gnomad4 FIN exome AF: 0.376

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.384 AC: 58289 AN: 151964 Hom.: 12144 Cov.: 32 AF XY: 0.379 AC XY: 28141 AN XY: 74266

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.397

Alfa AF: 0.435 Hom.: 7908

Bravo AF: 0.378

Asia WGS AF: 0.410 AC: 1426 AN: 3478

EpiCase AF: 0.472

EpiControl AF: 0.472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Thr257Thr in exon 6 of GNA11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 46.79% (31211/66704) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs4900). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs4900; hg19: chr19-3119239; COSMIC: COSV50020241; COSMIC: COSV50020241;