rs140930365

Variant names:

• chr6-32182579-A-T
• rs140930365
• NM_001136.5:c.811T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001136.5(AGER):​c.811T>A​(p.Trp271Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,612,934 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (8 hom.)
• Consequence: AGER NM_001136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.86
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073978603).
• BP6: Variant 6-32182579-A-T is Benign according to our data. Variant chr6-32182579-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 710267.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGER	NM_001136.5	MANE Select	c.811T>A	p.Trp271Arg	missense	Exon 7 of 11	NP_001127.1	Q15109-1
	AGER	NM_001206929.2		c.859T>A	p.Trp287Arg	missense	Exon 7 of 11	NP_001193858.1	Q15109-6
	AGER	NM_001206932.2		c.769T>A	p.Trp257Arg	missense	Exon 7 of 11	NP_001193861.1	Q15109-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGER	ENST00000375076.9	TSL:1 MANE Select	c.811T>A	p.Trp271Arg	missense	Exon 7 of 11	ENSP00000364217.4	Q15109-1
	AGER	ENST00000375069.7	TSL:1	c.859T>A	p.Trp287Arg	missense	Exon 7 of 11	ENSP00000364210.4	Q15109-6
	AGER	ENST00000438221.6	TSL:1	c.859T>A	p.Trp287Arg	missense	Exon 7 of 10	ENSP00000387887.2	Q15109-4

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152044 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00215 AC: 530 AN: 246552 AF XY: 0.00208

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00101 AC: 1474 AN: 1460772 Hom.: 8 Cov.: 34 AF XY: 0.00100 AC XY: 727 AN XY: 726706

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00349 AC: 156 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 798 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52316

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1112006

Other (OTH) AF: 0.00277 AC: 167 AN: 60386

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152162 Hom.: 4 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74396

African (AFR) AF: 0.000193 AC: 8 AN: 41510

American (AMR) AF: 0.00536 AC: 82 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67974

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00263 Hom.: 4

Bravo AF: 0.00165

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.000554 AC: 3

ExAC AF: 0.00147 AC: 173

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		2.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.84		Gain of disorder (P = 0.0059)
MVP		0.84
MPC		0.89
ClinPred		0.098	T
GERP RS		5.3
Varity_R		0.51
gMVP		0.92
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs140930365; hg19: chr6-32150356; COSMIC: COSV61248121; COSMIC: COSV61248121;