dbSNP rs4042056: IGHG3:p.Arg364His (chr14-105769277-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.662

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank
IGHG3	unassigned_transcript_2476	c.1091G>A	p.Arg364His	missense_variant	Exon 7 of 9
IGHG3	unassigned_transcript_2477	c.1091G>A	p.Arg364His	missense_variant	Exon 7 of 7
IGH		n.105769277C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHG3	ENST00000641136.1 link	c.1091G>A	p.Arg364His	missense_variant	Exon 7 of 9			ENSP00000492969.1		A0A9H4DHQ2
IGHG3	ENST00000390551.6 link	c.1091G>A	p.Arg364His	missense_variant	Exon 7 of 7	6		ENSP00000374993.2		A0A9H3ZR93

Frequencies

GnomAD3 genomes

AF:

0.0971

AC:

10827

AN:

111498

Hom.:

162

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0334

AC XY:

10946

AN XY:

327884

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

704

1409

2113

2818

3522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0973

AC:

10853

AN:

111546

Hom.:

165

Cov.:

AF XY:

0.104

AC XY:

5626

AN XY:

54138

show subpopulations

⚠️ 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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.353

Heterozygous variant carriers

754

1508

2263

3017

3771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.105

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over