chr1-1047342-A-G

Position:

• chr1-1047342-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.3404A>G​(p.Gln1135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00958 in 1,605,086 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (26 hom., cov: 34)
  • Exomes 𝑓: 0.0098 (255 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.00

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=0.007086724).
• BP6: Variant 1-1047342-A-G is Benign according to our data. Variant chr1-1047342-A-G is described in ClinVar as [Benign]. Clinvar id is 128299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1047342-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3404A>G	p.Gln1135Arg	missense_variant	20/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3404A>G	p.Gln1135Arg	missense_variant	20/36	1	NM_198576.4	ENSP00000368678	P1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1180 AN: 152210 Hom.: 26 Cov.: 34

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00866

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0130 AC: 3174 AN: 243754 Hom.: 80 AF XY: 0.0159 AC XY: 2100 AN XY: 132238

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00395

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00977 AC: 14198 AN: 1452758 Hom.: 255 Cov.: 32 AF XY: 0.0115 AC XY: 8280 AN XY: 722106

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00299

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.00439

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152328 Hom.: 26 Cov.: 34 AF XY: 0.00839 AC XY: 625 AN XY: 74488

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.0574

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00866

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00872 Hom.: 11

Bravo AF: 0.00612

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.0140 AC: 1697

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	This variant is associated with the following publications: (PMID: 31167812) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.0070	D;D
Vest4		0.52
MPC		0.59
ClinPred		0.013	T
GERP RS		4.2
gMVP		0.68

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: rs142416636; hg19: chr1-982722;