chr1-1046922-C-A

Position:

• chr1-1046922-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_198576.4(AGRN):​c.3353C>A​(p.Thr1118Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,579,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1118M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.50

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012785703).
• BP6: Variant 1-1046922-C-A is Benign according to our data. Variant chr1-1046922-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474116.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr1-1046922-C-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.3353C>A	p.Thr1118Lys	missense_variant	19/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.3353C>A	p.Thr1118Lys	missense_variant	19/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.3038C>A	p.Thr1013Lys	missense_variant	18/38
AGRN	ENST00000652369.1	c.3038C>A	p.Thr1013Lys	missense_variant	18/35
AGRN	ENST00000620552.4	c.2939C>A	p.Thr980Lys	missense_variant	19/39	5

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00187 AC: 356 AN: 190804 Hom.: 0 AF XY: 0.00190 AC XY: 194 AN XY: 102348

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000690

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000400

Gnomad FIN exome AF: 0.00868

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.000800

GnomAD4 exome AF: 0.00198 AC: 2824 AN: 1427234 Hom.: 1 Cov.: 39 AF XY: 0.00192 AC XY: 1354 AN XY: 706762

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000619

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000466

Gnomad4 FIN exome AF: 0.00732

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74456

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00117 AC: 140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24951643, 26290588) -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.74
MVP		0.89
MPC		0.63
ClinPred		0.024	T
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
gMVP		0.86

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: rs149159118; hg19: chr1-982302;