rs111818381

Variant names:

• chr1-1049591-G-A
• rs111818381
• NM_198576.4:c.4540G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1049591-G-A
• chr1-1049591-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001305275.2(AGRN):​c.4540G>A​(p.Ala1514Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,590,108 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1514A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (83 hom.)
• Consequence: AGRN NM_001305275.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.43
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0125926435).
• BP6: Variant 1-1049591-G-A is Benign according to our data. Variant chr1-1049591-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00762 (1160/152260) while in subpopulation NFE AF = 0.0114 (774/68008). AF 95% confidence interval is 0.0107. There are 9 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305275.2. 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
	AGRN	NM_198576.4	MANE Select	c.4540G>A	p.Ala1514Thr	missense	Exon 26 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.4540G>A	p.Ala1514Thr	missense	Exon 26 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.4225G>A	p.Ala1409Thr	missense	Exon 25 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4540G>A	p.Ala1514Thr	missense	Exon 26 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4225G>A	p.Ala1409Thr	missense	Exon 25 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4225G>A	p.Ala1409Thr	missense	Exon 25 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1162 AN: 152142 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00782 AC: 1602 AN: 204756 AF XY: 0.00788

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00506

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00966 AC: 13896 AN: 1437848 Hom.: 83 Cov.: 44 AF XY: 0.00953 AC XY: 6794 AN XY: 713080

African (AFR) AF: 0.00172 AC: 57 AN: 33192

American (AMR) AF: 0.00518 AC: 211 AN: 40712

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 627 AN: 25620

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38640

South Asian (SAS) AF: 0.00316 AC: 263 AN: 83212

European-Finnish (FIN) AF: 0.00495 AC: 247 AN: 49896

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5738

European-Non Finnish (NFE) AF: 0.0107 AC: 11824 AN: 1101370

Other (OTH) AF: 0.00992 AC: 590 AN: 59468

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152260 Hom.: 9 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74448

African (AFR) AF: 0.00248 AC: 103 AN: 41552

American (AMR) AF: 0.00608 AC: 93 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0114 AC: 774 AN: 68008

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0104 Hom.: 28

Bravo AF: 0.00801

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00184 AC: 8

ESP6500EA AF: 0.0110 AC: 94

ExAC AF: 0.00660 AC: 790

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.022
DANN	Benign	0.64
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N
PhyloP100		-1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.12
Sift	Benign	0.59	T
Sift4G	Benign	0.49	T
Vest4		0.029
MVP		0.53
MPC		0.12
ClinPred		0.00028	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.29
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: rs111818381; hg19: chr1-984971;