Genetic Variant AGRN:p.Asp1770Tyr (chr1-1051307-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198576.4(AGRN):c.5308G>T(p.Asp1770Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,419,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1770N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.42

Publications

0 publications found

Variant links:

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

AGRN Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.5308G>T	p.Asp1770Tyr	missense_variant	Exon 31 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.5308G>T	p.Asp1770Tyr	missense_variant	Exon 31 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1 link	c.5005G>T	p.Asp1669Tyr	missense_variant	Exon 31 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2 link	c.4993G>T	p.Asp1665Tyr	missense_variant	Exon 30 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4 link	c.4906G>T	p.Asp1636Tyr	missense_variant	Exon 32 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32770

American (AMR)

AF:

0.00

AC:

AN:

38570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.00

AC:

AN:

37790

South Asian (SAS)

AF:

0.00

AC:

AN:

80776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091556

Other (OTH)

AF:

0.00

AC:

AN:

58840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.0

.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0060

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.84

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.89

Mutation Taster

=34/66

disease causing

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over