rs535286672

Variant names:

• chr1-1050054-T-A
• rs535286672
• NM_198576.4:c.4879+17T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1050054-T-A
• chr1-1050054-T-C
• chr1-1050054-T-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.4879+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 859,976 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.260
• Publications: 0 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: ClinGen, 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 (BayesDel_noAF=-0.86).
• BP6: Variant 1-1050054-T-A is Benign according to our data. Variant chr1-1050054-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 263190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00161 (206/127868) while in subpopulation AFR AF = 0.00642 (191/29768). AF 95% confidence interval is 0.00567. There are 2 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4879+17T>A		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4879+17T>A		intron	N/A	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4564+17T>A		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.4879+17T>A		intron	N/A	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4564+17T>A		intron	N/A	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4564+17T>A		intron	N/A	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 205 AN: 127820 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000971

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000160

Gnomad OTH AF: 0.000561

GnomAD2 exomes AF: 0.000365 AC: 50 AN: 137146 AF XY: 0.000281

Gnomad AFR exome AF: 0.00653

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000281 AC: 206 AN: 732108 Hom.: 1 Cov.: 32 AF XY: 0.000223 AC XY: 84 AN XY: 376688

African (AFR) AF: 0.0122 AC: 153 AN: 12526

American (AMR) AF: 0.000478 AC: 15 AN: 31376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17116

East Asian (EAS) AF: 0.00 AC: 0 AN: 20714

South Asian (SAS) AF: 0.0000297 AC: 2 AN: 67286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33894

Middle Eastern (MID) AF: 0.000377 AC: 1 AN: 2656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 515512

Other (OTH) AF: 0.00113 AC: 35 AN: 31028

GnomAD4 genome AF: 0.00161 AC: 206 AN: 127868 Hom.: 2 Cov.: 32 AF XY: 0.00158 AC XY: 98 AN XY: 61920

African (AFR) AF: 0.00642 AC: 191 AN: 29768

American (AMR) AF: 0.000969 AC: 13 AN: 13412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3220

East Asian (EAS) AF: 0.00 AC: 0 AN: 3746

South Asian (SAS) AF: 0.00 AC: 0 AN: 3700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62646

Other (OTH) AF: 0.000555 AC: 1 AN: 1802

Alfa AF: 0.000940 Hom.: 1

Bravo AF: 0.00159

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.30
PhyloP100		-0.26

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs535286672; hg19: chr1-985434;