Genetic Variant AGER:c.992-6G>A (chr6-32181483-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 NM_001136.5(AGER):c.992-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,186 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.039 ( 267 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 365 hom. )

Consequence

AGER
NM_001136.5 splice_region, intron

Scores

Splicing: ADA: 0.00007161

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.0310

Publications

42 publications found

Variant links:

Genes affected

AGER (HGNC:320): (advanced glycosylation end-product specific receptor) The advanced glycosylation end product (AGE) receptor encoded by this gene is a member of the immunoglobulin superfamily of cell surface receptors. It is a multiligand receptor, and besides AGE, interacts with other molecules implicated in homeostasis, development, and inflammation, and certain diseases, such as diabetes and Alzheimer's disease. Many alternatively spliced transcript variants encoding different isoforms, as well as non-protein-coding variants, have been described for this gene (PMID:18089847). [provided by RefSeq, May 2011]

AGER links:

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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=-0.47).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGER	NM_001136.5 link	c.992-6G>A		splice_region_variant, intron_variant	Intron 9 of 10	ENST00000375076.9	NP_001127.1	Q15109-1A0A1U9X785B4DNX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGER	ENST00000375076.9 link	c.992-6G>A		splice_region_variant, intron_variant	Intron 9 of 10	1	NM_001136.5	ENSP00000364217.4		Q15109-1

Frequencies

GnomAD3 genomes

AF:

0.0392

AC:

5959

AN:

152146

Hom.:

267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.0366

Gnomad SAS

AF:

0.0267

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00487

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0189

AC:

4666

AN:

246984

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.0384

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00477

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.00953

AC:

13916

AN:

1460922

Hom.:

365

Cov.:

AF XY:

0.00973

AC XY:

7068

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.116

AC:

3872

AN:

33480

American (AMR)

AF:

0.0189

AC:

846

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

431

AN:

26136

East Asian (EAS)

AF:

0.0287

AC:

1140

AN:

39700

South Asian (SAS)

AF:

0.0274

AC:

2362

AN:

86258

European-Finnish (FIN)

AF:

0.000324

AC:

AN:

52464

Middle Eastern (MID)

AF:

0.0331

AC:

191

AN:

5766

European-Non Finnish (NFE)

AF:

0.00365

AC:

4057

AN:

1112010

Other (OTH)

AF:

0.0166

AC:

1000

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

892

1785

2677

3570

4462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.0392

AC:

5969

AN:

152264

Hom.:

267

Cov.:

AF XY:

0.0390

AC XY:

2903

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.111

AC:

4627

AN:

41536

American (AMR)

AF:

0.0346

AC:

530

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.0367

AC:

190

AN:

5176

South Asian (SAS)

AF:

0.0267

AC:

129

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00487

AC:

331

AN:

68020

Other (OTH)

AF:

0.0417

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

285

570

855

1140

1425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0138

Hom.:

275

Bravo

AF:

0.0456

Asia WGS

AF:

0.0360

AC:

127

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00688

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

COPD, severe early onset

Uncertain:1

Aug 10, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

2.9

(source)

DANN

Benign

0.77

PhyloP100

-0.031

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000072

dbscSNV1_RF

Benign

0.0060

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over