NM_001136.5:c.992-6G>A

Variant names:

• chr6-32181483-C-T
• rs2071288
• NM_001136.5:c.992-6G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136.5. 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
	AGER	NM_001136.5	MANE Select	c.992-6G>A		splice_region intron	N/A	NP_001127.1
	AGER	NM_001206929.2		c.1040-6G>A		splice_region intron	N/A	NP_001193858.1
	AGER	NM_001206932.2		c.950-6G>A		splice_region intron	N/A	NP_001193861.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGER	ENST00000375076.9	TSL:1 MANE Select	c.992-6G>A		splice_region intron	N/A	ENSP00000364217.4
	AGER	ENST00000375069.7	TSL:1	c.1040-6G>A		splice_region intron	N/A	ENSP00000364210.4
	AGER	ENST00000438221.6	TSL:1	c.*29+41G>A		intron	N/A	ENSP00000387887.2

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 5959 AN: 152146 Hom.: 267 Cov.: 32

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

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.: 31 AF XY: 0.00973 AC XY: 7068 AN XY: 726768

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: 17 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

GnomAD4 genome AF: 0.0392 AC: 5969 AN: 152264 Hom.: 267 Cov.: 32 AF XY: 0.0390 AC XY: 2903 AN XY: 74450

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: 63 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: 4 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 68020

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.9
DANN	Benign	0.77
PhyloP100		-0.031
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071288; hg19: chr6-32149260; COSMIC: COSV61247703; COSMIC: COSV61247703;