Genetic Variant IGHG3:p.Arg221Arg (chr14-105769804-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The ENST00000641136.1(IGHG3):c.661C>A(p.Arg221Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 627,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

IGHG3
ENST00000641136.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.756

Publications

0 publications found

Variant links:

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 links:

IGH (HGNC:5477):

IGH links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP7

Synonymous conserved (PhyloP=-0.756 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank
IGHG3	unassigned_transcript_2476	c.661C>A	p.Arg221Arg	synonymous_variant	Exon 6 of 9
IGHG3	unassigned_transcript_2477	c.661C>A	p.Arg221Arg	synonymous_variant	Exon 6 of 7
IGH		n.105769804G>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHG3	ENST00000641136.1 link	c.661C>A	p.Arg221Arg	synonymous_variant	Exon 6 of 9			ENSP00000492969.1		A0A9H4DHQ2
IGHG3	ENST00000390551.6 link	c.661C>A	p.Arg221Arg	synonymous_variant	Exon 6 of 7	6		ENSP00000374993.2		A0A9H3ZR93

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000159

AC:

AN:

627480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

341872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17658

American (AMR)

AF:

0.00

AC:

AN:

43702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20914

East Asian (EAS)

AF:

0.00

AC:

AN:

36064

South Asian (SAS)

AF:

0.00

AC:

AN:

69752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3590

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

349702

Other (OTH)

AF:

0.00

AC:

AN:

32972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

1.2

(source)

DANN

Benign

0.38

PhyloP100

-0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over