14-105742782-T-G

Variant names:

• chr14-105742782-T-G
• rs1071803
• ENST00000390548.6:c.290A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000390548.6(IGHG1):​c.290A>C​(p.Lys97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 777,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: IGHG1 ENST00000390548.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.11
• Publications: 13 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).

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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHG1	ENST00000390548.6	TSL:6	c.290A>C	p.Lys97Thr	missense	Exon 1 of 6	ENSP00000374990.2
	IGHG1	ENST00000390549.6	TSL:6	c.290A>C	p.Lys97Thr	missense	Exon 1 of 4	ENSP00000374991.2
	IGHG1	ENST00000390542.6	TSL:6	c.290A>C	p.Lys97Thr	missense	Exon 1 of 5	ENSP00000374984.2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151534 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000329 AC: 8 AN: 243152 AF XY: 0.00000758

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000552

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000463 AC: 29 AN: 626234 Hom.: 0 Cov.: 0 AF XY: 0.0000410 AC XY: 14 AN XY: 341246

African (AFR) AF: 0.000114 AC: 2 AN: 17616

American (AMR) AF: 0.0000457 AC: 2 AN: 43718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20950

East Asian (EAS) AF: 0.0000555 AC: 2 AN: 36046

South Asian (SAS) AF: 0.0000718 AC: 5 AN: 69684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2514

European-Non Finnish (NFE) AF: 0.0000515 AC: 18 AN: 349696

Other (OTH) AF: 0.00 AC: 0 AN: 32884

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151534 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73922

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

African (AFR) AF: 0.0000969 AC: 4 AN: 41278

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00584209), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000248 Hom.: 8879

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0010
DANN	Benign	0.52
PhyloP100		-2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1071803; hg19: chr14-106209119;