chr1-1050417-A-G

Variant names:

• chr1-1050417-A-G
• rs142286944
• NM_198576.4:c.4977-10A>G

Variant summary

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

The NM_198576.4(AGRN):​c.4977-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,612,724 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (51 hom., cov: 33)
  • Exomes 𝑓: 0.026 (604 hom.)
• Consequence: AGRN NM_198576.4 intron
• Scores: Splicing: ADA: 0.00002238
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27
• Publications: 3 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: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.88).
• BP6: Variant 1-1050417-A-G is Benign according to our data. Variant chr1-1050417-A-G is described in ClinVar as Benign. ClinVar VariationId is 263193.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 = 0.0185 (2807/152140) while in subpopulation NFE AF = 0.0304 (2068/67924). AF 95% confidence interval is 0.0294. There are 51 homozygotes in GnomAd4. There are 1299 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.4977-10A>G		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4977-10A>G		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4662-10A>G		intron	N/A	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4977-10A>G		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4662-10A>G		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4662-10A>G		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2812 AN: 152022 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0184 AC: 4542 AN: 247310 AF XY: 0.0191

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00834

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00979

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0265 AC: 38659 AN: 1460584 Hom.: 604 Cov.: 34 AF XY: 0.0265 AC XY: 19230 AN XY: 726614

African (AFR) AF: 0.00373 AC: 125 AN: 33478

American (AMR) AF: 0.00862 AC: 385 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 477 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0207 AC: 1784 AN: 86254

European-Finnish (FIN) AF: 0.00934 AC: 489 AN: 52362

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5766

European-Non Finnish (NFE) AF: 0.0304 AC: 33828 AN: 1111878

Other (OTH) AF: 0.0247 AC: 1491 AN: 60372

GnomAD4 genome AF: 0.0185 AC: 2807 AN: 152140 Hom.: 51 Cov.: 33 AF XY: 0.0175 AC XY: 1299 AN XY: 74374

African (AFR) AF: 0.00462 AC: 192 AN: 41526

American (AMR) AF: 0.0116 AC: 178 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0242 AC: 117 AN: 4828

European-Finnish (FIN) AF: 0.00923 AC: 98 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2068 AN: 67924

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.0233 Hom.: 13

Bravo AF: 0.0173

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.86
DANN	Benign	0.45
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
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: rs142286944; hg19: chr1-985797;