chr1-1041158-A-C

Variant names:

• chr1-1041158-A-C
• rs550290966
• NM_198576.4:c.728-15A>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_198576.4(AGRN):​c.728-15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,379,574 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161

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]

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-1041158-A-C is Benign according to our data. Variant chr1-1041158-A-C is described in ClinVar as [Benign]. Clinvar id is 1652233.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 = 0.00195 (294/150400) while in subpopulation AFR AF = 0.00691 (283/40964). AF 95% confidence interval is 0.00625. There are 4 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.728-15A>C		intron_variant	Intron 4 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.728-15A>C		intron_variant	Intron 4 of 35	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 292 AN: 150290 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000528

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: 0.0000445

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000301 AC: 10 AN: 33240 AF XY: 0.000100

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000351

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: 0.000131 AC: 161 AN: 1229174 Hom.: 1 Cov.: 33 AF XY: 0.000118 AC XY: 71 AN XY: 602054

African (AFR) AF: 0.00537 AC: 129 AN: 24030

American (AMR) AF: 0.000251 AC: 4 AN: 15924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18580

East Asian (EAS) AF: 0.00 AC: 0 AN: 25586

South Asian (SAS) AF: 0.0000505 AC: 3 AN: 59452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30346

Middle Eastern (MID) AF: 0.000844 AC: 3 AN: 3556

European-Non Finnish (NFE) AF: 0.00000898 AC: 9 AN: 1001860

Other (OTH) AF: 0.000261 AC: 13 AN: 49840

GnomAD4 genome AF: 0.00195 AC: 294 AN: 150400 Hom.: 4 Cov.: 31 AF XY: 0.00200 AC XY: 147 AN XY: 73508

African (AFR) AF: 0.00691 AC: 283 AN: 40964

American (AMR) AF: 0.000527 AC: 8 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67428

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00242 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome 8 Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.17
PhyloP100		-0.16
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs550290966; hg19: chr1-976538;