14-105741745-G-T

Variant names:

• chr14-105741745-G-T
• rs11621259
• ENST00000390548.6:c.721C>A

Variant summary

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

The ENST00000390548.6(IGHG1):​c.721C>A​(p.Leu241Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 734,134 control chromosomes in the GnomAD database, including 137,999 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 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 0.47 (21452 hom., cov: 26)
  • Exomes 𝑓: 0.57 (116547 hom.)
• Consequence: IGHG1 ENST00000390548.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 5 publications found

Genes affected

IGHG1 (HGNC:5525): (immunoglobulin heavy constant gamma 1 (G1m marker)) Predicted to enable antigen binding activity and immunoglobulin receptor binding activity. Predicted to be involved in several processes, including activation of immune response; defense response to other organism; and phagocytosis. Predicted to act upstream of or within several processes, including immunoglobulin mediated immune response; positive regulation of hypersensitivity; and positive regulation of phagocytosis. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

IGHG1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

IGH (HGNC:5477):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000390548.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHG1	ENST00000390548.6	TSL:6	c.721C>A	p.Leu241Met	missense	Exon 4 of 6	ENSP00000374990.2
	IGHG1	ENST00000390549.6	TSL:6	c.721C>A	p.Leu241Met	missense	Exon 4 of 4	ENSP00000374991.2
	IGHG1	ENST00000390542.6	TSL:6	c.616C>A	p.Leu206Met	missense	Exon 5 of 5	ENSP00000374984.2

Frequencies

GnomAD3 genomes AF: 0.470 AC: 69633 AN: 148088 Hom.: 21459 Cov.: 26

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.365 AC: 67341 AN: 184476 AF XY: 0.378

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.00647

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.413

GnomAD4 exome AF: 0.575 AC: 336842 AN: 585916 Hom.: 116547 Cov.: 0 AF XY: 0.585 AC XY: 185459 AN XY: 316978

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

African (AFR) AF: 0.0991 AC: 1684 AN: 16994

American (AMR) AF: 0.254 AC: 9534 AN: 37606

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 14557 AN: 18652

East Asian (EAS) AF: 0.00775 AC: 279 AN: 35996

South Asian (SAS) AF: 0.494 AC: 30718 AN: 62162

European-Finnish (FIN) AF: 0.596 AC: 30114 AN: 50530

Middle Eastern (MID) AF: 0.647 AC: 1789 AN: 2764

European-Non Finnish (NFE) AF: 0.699 AC: 230774 AN: 330180

Other (OTH) AF: 0.560 AC: 17393 AN: 31032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.470 AC: 69611 AN: 148218 Hom.: 21452 Cov.: 26 AF XY: 0.458 AC XY: 33037 AN XY: 72074

African (AFR) AF: 0.120 AC: 4835 AN: 40402

American (AMR) AF: 0.405 AC: 6012 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2627 AN: 3396

East Asian (EAS) AF: 0.0169 AC: 83 AN: 4914

South Asian (SAS) AF: 0.435 AC: 1959 AN: 4504

European-Finnish (FIN) AF: 0.581 AC: 5986 AN: 10300

Middle Eastern (MID) AF: 0.640 AC: 174 AN: 272

European-Non Finnish (NFE) AF: 0.694 AC: 46227 AN: 66648

Other (OTH) AF: 0.503 AC: 1034 AN: 2056

Alfa AF: 0.483 Hom.: 4257

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.91
DANN	Benign	0.76
PhyloP100		-2.1

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: rs11621259; hg19: chr14-106208082;