Genetic Variant ENST00000641136.1:c.661C>T (chr14-105769806-G-A) – 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.659C>T(p.Pro220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 777,512 control chromosomes in the GnomAD database, including 47,896 homozygotes. 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 0.26 ( 6740 hom., cov: 32)

Exomes 𝑓: 0.33 ( 41156 hom. )

Consequence

IGHG3
ENST00000641136.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.02

Publications

9 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=-0.87).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank
IGHG3	unassigned_transcript_2476	c.659C>T	p.Pro220Leu	missense_variant	Exon 6 of 9
IGHG3	unassigned_transcript_2477	c.659C>T	p.Pro220Leu	missense_variant	Exon 6 of 7
IGH		n.105769806G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHG3	ENST00000641136.1 link	c.659C>T	p.Pro220Leu	missense_variant	Exon 6 of 9			ENSP00000492969.1		A0A9H4DHQ2
IGHG3	ENST00000390551.6 link	c.659C>T	p.Pro220Leu	missense_variant	Exon 6 of 7	6		ENSP00000374993.2		A0A9H3ZR93

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39198

AN:

150060

Hom.:

6728

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0696

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.367

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.202

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.269

GnomAD2 exomes

AF:

0.351

AC:

86454

AN:

246288

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.0597

Gnomad AMR exome

AF:

0.622

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.413

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.338

GnomAD4 exome

AF:

0.335

AC:

210007

AN:

627362

Hom.:

41156

Cov.:

AF XY:

0.328

AC XY:

112273

AN XY:

341834

show subpopulations

African (AFR)

AF:

0.0679

AC:

1199

AN:

17660

American (AMR)

AF:

0.605

AC:

26440

AN:

43684

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

4175

AN:

20894

East Asian (EAS)

AF:

0.534

AC:

19240

AN:

36062

South Asian (SAS)

AF:

0.347

AC:

24220

AN:

69750

European-Finnish (FIN)

AF:

0.401

AC:

21302

AN:

53124

Middle Eastern (MID)

AF:

0.224

AC:

811

AN:

3616

European-Non Finnish (NFE)

AF:

0.294

AC:

102659

AN:

349606

Other (OTH)

AF:

0.302

AC:

9961

AN:

32966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

11166

22332

33499

44665

55831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<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

AF:

0.261

AC:

39221

AN:

150150

Hom.:

6740

Cov.:

AF XY:

0.275

AC XY:

20127

AN XY:

73208

show subpopulations

African (AFR)

AF:

0.0696

AC:

2848

AN:

40936

American (AMR)

AF:

0.477

AC:

7051

AN:

14784

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

695

AN:

3470

East Asian (EAS)

AF:

0.368

AC:

1765

AN:

4802

South Asian (SAS)

AF:

0.378

AC:

1739

AN:

4606

European-Finnish (FIN)

AF:

0.410

AC:

4339

AN:

10594

Middle Eastern (MID)

AF:

0.215

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.295

AC:

19951

AN:

67726

Other (OTH)

AF:

0.269

AC:

558

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1331

2661

3992

5322

6653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.277

Hom.:

2101

Bravo

AF:

0.262

Asia WGS

AF:

0.346

AC:

1193

AN:

3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.3

(source)

DANN

Benign

0.73

PhyloP100

-2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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