rs74093865

Positions:

• chr14-105769806-G-A
• chr14-105769806-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000641136.1(IGHG3):​c.662C>T​(p.Pro221Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 777,512 control chromosomes in the GnomAD database, including 47,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6740 hom., cov: 32)
  • Exomes 𝑓: 0.33 (41156 hom.)
• Consequence: IGHG3 ENST00000641136.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02

Genes affected

IGHG3 (HGNC:5527): (immunoglobulin heavy constant gamma 3 (G3m marker)) Predicted to enable antigen binding activity and immunoglobulin receptor binding activity. Involved in retina homeostasis. Located in blood microparticle and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHG3	ENST00000641136.1	c.662C>T	p.Pro221Leu	missense_variant	6/9			ENSP00000492969	P5
IGHG3	ENST00000390551.6	c.662C>T	p.Pro221Leu	missense_variant	6/7			ENSP00000374993	A2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39198 AN: 150060 Hom.: 6728 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.351 AC: 86454 AN: 246288 Hom.: 18658 AF XY: 0.342 AC XY: 45821 AN XY: 133842

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.362

Gnomad SAS exome AF: 0.379

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.335 AC: 210007 AN: 627362 Hom.: 41156 Cov.: 0 AF XY: 0.328 AC XY: 112273 AN XY: 341834

Gnomad4 AFR exome AF: 0.0679

Gnomad4 AMR exome AF: 0.605

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.534

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.294

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.261 AC: 39221 AN: 150150 Hom.: 6740 Cov.: 32 AF XY: 0.275 AC XY: 20127 AN XY: 73208

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.269

Alfa AF: 0.277 Hom.: 2101

Bravo AF: 0.262

Asia WGS AF: 0.346 AC: 1193 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs74093865; hg19: chr14-106236143;