rs60746425

Positions:

• chr14-105769804-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000641136.1(IGHG3):​c.661C>T​(p.Arg221Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 777,922 control chromosomes in the GnomAD database, including 1,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/5 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 0.0083 (69 hom., cov: 32)
  • Exomes 𝑓: 0.025 (1146 hom.)
• Consequence: IGHG3 ENST00000641136.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.756

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]

IGHG3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHG3	unassigned_transcript_2476	c.661C>T	p.Arg221Trp	missense_variant	6/9
IGHG3	unassigned_transcript_2477	c.661C>T	p.Arg221Trp	missense_variant	6/7
IGH		n.105769804G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHG3	ENST00000641136.1	c.661C>T	p.Arg221Trp	missense_variant	6/9			ENSP00000492969.1
IGHG3	ENST00000390551.6	c.661C>T	p.Arg221Trp	missense_variant	6/7	6		ENSP00000374993.2

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1252 AN: 150360 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00835

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0918

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0233

Gnomad NFE AF: 0.00299

Gnomad OTH AF: 0.0136

GnomAD3 exomes AF: 0.0201 AC: 4962 AN: 246430 Hom.: 207 AF XY: 0.0227 AC XY: 3037 AN XY: 133904

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.0650

Gnomad SAS exome AF: 0.0775

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0246 AC: 15432 AN: 627480 Hom.: 1146 Cov.: 0 AF XY: 0.0273 AC XY: 9325 AN XY: 341872

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.0820

Gnomad4 FIN exome AF: 0.00405

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.00828 AC: 1246 AN: 150442 Hom.: 69 Cov.: 32 AF XY: 0.0101 AC XY: 738 AN XY: 73378

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.00821

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.0922

Gnomad4 SAS AF: 0.0651

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0125

Alfa AF: 0.00593 Hom.: 1

Bravo AF: 0.00729

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs60746425; hg19: chr14-106236141;