rs1045853

Variant names:

• chr14-105741749-A-C
• rs1045853
• ENST00000390548.6:c.717T>G
• IGHG1 p.Asp239Glu

Your query was ambiguous. Multiple possible variants found:

• chr14-105741749-A-C
• chr14-105741749-A-G
• chr14-105741749-A-T

Variant summary

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

The ENST00000390548.6(IGHG1):​c.717T>G​(p.Asp239Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 733,814 control chromosomes in the GnomAD database, including 138,915 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 (21508 hom., cov: 26)
  • Exomes 𝑓: 0.58 (117407 hom.)
• Consequence: IGHG1 ENST00000390548.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.34
• Publications: 9 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=-1.05).
• 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

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
	IGHG1	ENST00000390548.6	TSL:6	c.717T>G	p.Asp239Glu	missense	Exon 4 of 6	ENSP00000374990.2	P01857-2
	IGHG1	ENST00000390549.6	TSL:6	c.717T>G	p.Asp239Glu	missense	Exon 4 of 4	ENSP00000374991.2	P01857-1
	IGHG1	ENST00000390542.6	TSL:6	c.612T>G	p.Asp204Glu	missense	Exon 5 of 5	ENSP00000374984.2	A0A0A0MS07

Frequencies

GnomAD3 genomes AF: 0.471 AC: 69790 AN: 148086 Hom.: 21515 Cov.: 26

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.388 AC: 72245 AN: 186100 AF XY: 0.403

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.543

Gnomad EAS exome AF: 0.00658

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.578 AC: 338721 AN: 585600 Hom.: 117407 Cov.: 0 AF XY: 0.589 AC XY: 186586 AN XY: 317000

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

African (AFR) AF: 0.101 AC: 1715 AN: 16956

American (AMR) AF: 0.265 AC: 9765 AN: 36850

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 14717 AN: 18680

East Asian (EAS) AF: 0.00789 AC: 284 AN: 36004

South Asian (SAS) AF: 0.502 AC: 31095 AN: 61940

European-Finnish (FIN) AF: 0.597 AC: 30192 AN: 50604

Middle Eastern (MID) AF: 0.649 AC: 1906 AN: 2936

European-Non Finnish (NFE) AF: 0.700 AC: 231552 AN: 330590

Other (OTH) AF: 0.564 AC: 17495 AN: 31040

⚠️ 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: 0.471 AC: 69767 AN: 148214 Hom.: 21508 Cov.: 26 AF XY: 0.459 AC XY: 33133 AN XY: 72130

African (AFR) AF: 0.120 AC: 4840 AN: 40250

American (AMR) AF: 0.406 AC: 6029 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2634 AN: 3402

East Asian (EAS) AF: 0.0176 AC: 86 AN: 4892

South Asian (SAS) AF: 0.437 AC: 1978 AN: 4522

European-Finnish (FIN) AF: 0.583 AC: 6007 AN: 10302

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

European-Non Finnish (NFE) AF: 0.694 AC: 46313 AN: 66756

Other (OTH) AF: 0.503 AC: 1035 AN: 2058

Alfa AF: 0.403 Hom.: 4678

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0020
DANN	Benign	0.47
PhyloP100		-7.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1045853;

hg19: chr14-106208086;