rs144245019

Variant names:

• chr1-1051352-G-A
• rs144245019
• NM_198576.4:c.5353G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1051352-G-A
• chr1-1051352-G-C
• chr1-1051352-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198576.4(AGRN):​c.5353G>A​(p.Asp1785Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,566,410 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1785H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (86 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0220
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0104987025).
• BP6: Variant 1-1051352-G-A is Benign according to our data. Variant chr1-1051352-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128314.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00677 (1030/152056) while in subpopulation NFE AF = 0.0115 (778/67918). AF 95% confidence interval is 0.0108. There are 1 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 86 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. 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
	AGRN	NM_198576.4	MANE Select	c.5353G>A	p.Asp1785Asn	missense	Exon 31 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5365G>A	p.Asp1789Asn	missense	Exon 32 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.5050G>A	p.Asp1684Asn	missense	Exon 31 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5353G>A	p.Asp1785Asn	missense	Exon 31 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.5050G>A	p.Asp1684Asn	missense	Exon 31 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.5038G>A	p.Asp1680Asn	missense	Exon 30 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1031 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00237

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00633 AC: 1089 AN: 172002 AF XY: 0.00614

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00624

GnomAD4 exome AF: 0.00980 AC: 13859 AN: 1414354 Hom.: 86 Cov.: 37 AF XY: 0.00972 AC XY: 6798 AN XY: 699158

African (AFR) AF: 0.00140 AC: 46 AN: 32810

American (AMR) AF: 0.00476 AC: 179 AN: 37580

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 179 AN: 25268

East Asian (EAS) AF: 0.00 AC: 0 AN: 37760

South Asian (SAS) AF: 0.00117 AC: 94 AN: 80550

European-Finnish (FIN) AF: 0.00271 AC: 129 AN: 47546

Middle Eastern (MID) AF: 0.00334 AC: 18 AN: 5392

European-Non Finnish (NFE) AF: 0.0117 AC: 12765 AN: 1088810

Other (OTH) AF: 0.00766 AC: 449 AN: 58638

GnomAD4 genome AF: 0.00677 AC: 1030 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.00601 AC XY: 447 AN XY: 74350

African (AFR) AF: 0.00231 AC: 96 AN: 41512

American (AMR) AF: 0.00503 AC: 77 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00237 AC: 25 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 778 AN: 67918

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00933 Hom.: 9

Bravo AF: 0.00710

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00230 AC: 10

ESP6500EA AF: 0.0116 AC: 99

ExAC AF: 0.00511 AC: 595

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.5
DANN	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.022
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.069
Sift	Benign	0.56	T
Sift4G	Benign	0.48	T
Vest4		0.18
MVP		0.48
MPC		0.12
ClinPred		0.0023	T
GERP RS		-2.1
gMVP		0.38
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs144245019; hg19: chr1-986732; COSMIC: COSV99062175; COSMIC: COSV99062175;