rs4042056

Variant names:

• chr14-105769277-C-T
• rs4042056
• ENST00000641136.1:c.1091G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000641136.1(IGHG3):​c.1091G>A​(p.Arg364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.097 (165 hom., cov: 31)
  • Exomes 𝑓: 0.031 (1362 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGHG3 ENST00000641136.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.662
• Publications: 8 publications found

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]

IGH (HGNC:5477):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000641136.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHG3	ENST00000641136.1		c.1091G>A	p.Arg364His	missense	Exon 7 of 9	ENSP00000492969.1	A0A9H4DHQ2
	IGHG3	ENST00000390551.6	TSL:6	c.1091G>A	p.Arg364His	missense	Exon 7 of 7	ENSP00000374993.2	A0A9H3ZR93

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 10827 AN: 111498 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0218

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0394

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0870

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0914

GnomAD2 exomes AF: 0.0358 AC: 7426 AN: 207580 AF XY: 0.0368

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.0814

Gnomad FIN exome AF: 0.0621

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0306 AC: 18364 AN: 600176 Hom.: 1362 Cov.: 0 AF XY: 0.0334 AC XY: 10946 AN XY: 327884

African (AFR) AF: 0.0590 AC: 981 AN: 16640

American (AMR) AF: 0.0221 AC: 884 AN: 40032

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 334 AN: 20588

East Asian (EAS) AF: 0.233 AC: 6942 AN: 29780

South Asian (SAS) AF: 0.0989 AC: 6606 AN: 66788

European-Finnish (FIN) AF: 0.00609 AC: 296 AN: 48620

Middle Eastern (MID) AF: 0.0456 AC: 149 AN: 3270

European-Non Finnish (NFE) AF: 0.00442 AC: 1514 AN: 342616

Other (OTH) AF: 0.0207 AC: 658 AN: 31842

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0973 AC: 10853 AN: 111546 Hom.: 165 Cov.: 31 AF XY: 0.104 AC XY: 5626 AN XY: 54138

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.163 AC: 4484 AN: 27442

American (AMR) AF: 0.167 AC: 1800 AN: 10808

Ashkenazi Jewish (ASJ) AF: 0.0394 AC: 112 AN: 2840

East Asian (EAS) AF: 0.232 AC: 850 AN: 3664

South Asian (SAS) AF: 0.218 AC: 732 AN: 3354

European-Finnish (FIN) AF: 0.0557 AC: 443 AN: 7952

Middle Eastern (MID) AF: 0.0920 AC: 16 AN: 174

European-Non Finnish (NFE) AF: 0.0425 AC: 2255 AN: 53002

Other (OTH) AF: 0.0920 AC: 145 AN: 1576

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.105 Hom.: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	16
DANN	Benign	0.12
PhyloP100		0.66

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

Other links and lift over

dbSNP: rs4042056; hg19: chr14-106235614;