chr1-1049070-A-T

Variant names:

• chr1-1049070-A-T
• rs369279324
• NM_198576.4:c.4298+11A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_198576.4(AGRN):​c.4298+11A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.91
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-1049070-A-T is Benign according to our data. Variant chr1-1049070-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4298+11A>T		intron	N/A	NP_940978.2
	AGRN	NM_001305275.2		c.4298+11A>T		intron	N/A	NP_001292204.1
	AGRN	NM_001364727.2		c.3983+11A>T		intron	N/A	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.4298+11A>T		intron	N/A	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.3983+11A>T		intron	N/A	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.3983+11A>T		intron	N/A	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.0000594 AC: 7 AN: 117862 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000348

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000504 AC: 5 AN: 99240 AF XY: 0.0000363

Gnomad AFR exome AF: 0.000834

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000140

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000342

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000118 AC: 109 AN: 927316 Hom.: 0 Cov.: 37 AF XY: 0.000124 AC XY: 58 AN XY: 466668

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00142 AC: 26 AN: 18374

American (AMR) AF: 0.00 AC: 0 AN: 30942

Ashkenazi Jewish (ASJ) AF: 0.0000539 AC: 1 AN: 18564

East Asian (EAS) AF: 0.0000402 AC: 1 AN: 24898

South Asian (SAS) AF: 0.0000441 AC: 3 AN: 68030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33408

Middle Eastern (MID) AF: 0.000720 AC: 2 AN: 2778

European-Non Finnish (NFE) AF: 0.000101 AC: 70 AN: 691616

Other (OTH) AF: 0.000155 AC: 6 AN: 38706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000594 AC: 7 AN: 117944 Hom.: 0 Cov.: 23 AF XY: 0.0000536 AC XY: 3 AN XY: 55978

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000172 AC: 5 AN: 29020

American (AMR) AF: 0.00 AC: 0 AN: 11486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2970

East Asian (EAS) AF: 0.00 AC: 0 AN: 3954

South Asian (SAS) AF: 0.00 AC: 0 AN: 3492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000348 AC: 2 AN: 57524

Other (OTH) AF: 0.00 AC: 0 AN: 1658

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00583 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 06, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome 8 Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0060
DANN	Benign	0.20
PhyloP100		-2.9

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: rs369279324; hg19: chr1-984450;