rs116586548

Positions:

• chr1-1043248-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198576.4(AGRN):​c.1394C>T​(p.Pro465Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,605,312 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P465P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.600

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007951736).
• BP6: Variant 1-1043248-C-T is Benign according to our data. Variant chr1-1043248-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263161.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00211 (321/152238) while in subpopulation AFR AF= 0.00677 (281/41530). AF 95% confidence interval is 0.00612. There are 1 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1394C>T	p.Pro465Leu	missense_variant	8/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1394C>T	p.Pro465Leu	missense_variant	8/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1079C>T	p.Pro360Leu	missense_variant	7/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.1079C>T	p.Pro360Leu	missense_variant	7/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.980C>T	p.Pro327Leu	missense_variant	8/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000570 AC: 133 AN: 233148 Hom.: 0 AF XY: 0.000404 AC XY: 51 AN XY: 126184

Gnomad AFR exome AF: 0.00675

Gnomad AMR exome AF: 0.000676

Gnomad ASJ exome AF: 0.000313

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000570

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000277 AC: 403 AN: 1453074 Hom.: 3 Cov.: 35 AF XY: 0.000278 AC XY: 201 AN XY: 722018

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.000696

Gnomad4 ASJ exome AF: 0.000271

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000474

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000433

Gnomad4 OTH exome AF: 0.000649

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00193 AC XY: 144 AN XY: 74444

Gnomad4 AFR AF: 0.00677

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.00221

ESP6500AA AF: 0.00615 AC: 27

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000604 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 06, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.73
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.14
Sift	Benign	0.17	T;.
Sift4G	Benign	0.10	T;T
Vest4		0.26
MVP		0.74
MPC		1.0
ClinPred		0.030	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs116586548; hg19: chr1-978628;