1-1041648-G-T

Position:

• chr1-1041648-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.1123G>T​(p.Ala375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,611,148 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A375T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0067 (36 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.49

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054303408).
• BP6: Variant 1-1041648-G-T is Benign according to our data. Variant chr1-1041648-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 263158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1041648-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00518 (788/152180) while in subpopulation NFE AF= 0.00694 (472/67966). AF 95% confidence interval is 0.00643. There are 2 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1123G>T	p.Ala375Ser	missense_variant	6/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1123G>T	p.Ala375Ser	missense_variant	6/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.808G>T	p.Ala270Ser	missense_variant	5/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.808G>T	p.Ala270Ser	missense_variant	5/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.709G>T	p.Ala237Ser	missense_variant	6/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 787 AN: 152064 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00694

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00493 AC: 1175 AN: 238246 Hom.: 4 AF XY: 0.00520 AC XY: 683 AN XY: 131312

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.00233

Gnomad FIN exome AF: 0.00330

Gnomad NFE exome AF: 0.00699

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00671 AC: 9794 AN: 1458968 Hom.: 36 Cov.: 33 AF XY: 0.00666 AC XY: 4836 AN XY: 725714

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00412

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00254

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00752

Gnomad4 OTH exome AF: 0.00707

GnomAD4 genome AF: 0.00518 AC: 788 AN: 152180 Hom.: 2 Cov.: 31 AF XY: 0.00458 AC XY: 341 AN XY: 74408

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00694

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00681 Hom.: 10

Bravo AF: 0.00574

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000945 AC: 4

ESP6500EA AF: 0.00706 AC: 59

ExAC AF: 0.00466 AC: 560

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.00834

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	This variant is associated with the following publications: (PMID: 27378695) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	AGRN: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 02, 2017	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Benign, for Myasthenic syndrome, congenital, 8, autosomal recessive. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.27
Sift	Uncertain	0.022	D;.
Sift4G	Benign	0.42	T;T
Vest4		0.46
MVP		0.71
MPC		0.94
ClinPred		0.023	T
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs138031468; hg19: chr1-977028; COSMIC: COSV65070842; COSMIC: COSV65070842;