NM_198576.4:c.*19C>T

Variant names:

• chr1-1055000-C-T
• rs3121561
• NM_198576.4:c.*19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.*19C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,546,620 control chromosomes in the GnomAD database, including 71,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10257 hom., cov: 35)
  • Exomes 𝑓: 0.29 (60763 hom.)
• Consequence: AGRN NM_198576.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.413
• Publications: 9 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

ENSG00000242590 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-1055000-C-T is Benign according to our data. Variant chr1-1055000-C-T is described in ClinVar as Benign. ClinVar VariationId is 263157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

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.*19C>T		3_prime_UTR	Exon 36 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.*19C>T		3_prime_UTR	Exon 39 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.*19C>T		3_prime_UTR	Exon 36 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.*19C>T		3_prime_UTR	Exon 36 of 36	ENSP00000368678.2
	AGRN	ENST00000461111.1	TSL:1	n.2273C>T		non_coding_transcript_exon	Exon 3 of 3
	AGRN	ENST00000651234.1		c.*19C>T		3_prime_UTR	Exon 38 of 38	ENSP00000499046.1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53401 AN: 152020 Hom.: 10237 Cov.: 35

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.347

GnomAD2 exomes AF: 0.291 AC: 43425 AN: 149096 AF XY: 0.292

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.291 AC: 406267 AN: 1394482 Hom.: 60763 Cov.: 41 AF XY: 0.292 AC XY: 200824 AN XY: 687958

African (AFR) AF: 0.513 AC: 16173 AN: 31550

American (AMR) AF: 0.221 AC: 7904 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 7775 AN: 25160

East Asian (EAS) AF: 0.167 AC: 5969 AN: 35730

South Asian (SAS) AF: 0.311 AC: 24602 AN: 79194

European-Finnish (FIN) AF: 0.347 AC: 15830 AN: 45570

Middle Eastern (MID) AF: 0.286 AC: 1456 AN: 5088

European-Non Finnish (NFE) AF: 0.286 AC: 308995 AN: 1078574

Other (OTH) AF: 0.303 AC: 17563 AN: 57884

GnomAD4 genome AF: 0.351 AC: 53463 AN: 152138 Hom.: 10257 Cov.: 35 AF XY: 0.351 AC XY: 26083 AN XY: 74372

African (AFR) AF: 0.508 AC: 21068 AN: 41510

American (AMR) AF: 0.253 AC: 3877 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3472

East Asian (EAS) AF: 0.183 AC: 947 AN: 5170

South Asian (SAS) AF: 0.318 AC: 1535 AN: 4824

European-Finnish (FIN) AF: 0.361 AC: 3824 AN: 10586

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20022 AN: 67962

Other (OTH) AF: 0.345 AC: 727 AN: 2108

Alfa AF: 0.308 Hom.: 2925

Bravo AF: 0.349

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3121561; hg19: chr1-990380; COSMIC: COSV65069616; COSMIC: COSV65069616;