chr1-1043594-G-A

Position:

• chr1-1043594-G-A

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.1660G>A​(p.Val554Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,605,018 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (51 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.44

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=0.017632931).
• BP6: Variant 1-1043594-G-A is Benign according to our data. Variant chr1-1043594-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1043594-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00721 (1098/152322) while in subpopulation EAS AF= 0.0328 (170/5184). AF 95% confidence interval is 0.0288. There are 14 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1660G>A	p.Val554Met	missense_variant	9/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1660G>A	p.Val554Met	missense_variant	9/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.1345G>A	p.Val449Met	missense_variant	8/38
AGRN	ENST00000652369.1	c.1345G>A	p.Val449Met	missense_variant	8/35
AGRN	ENST00000620552.4	c.1246G>A	p.Val416Met	missense_variant	9/39	5

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1098 AN: 152204 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00656

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00811 AC: 1933 AN: 238454 Hom.: 22 AF XY: 0.00804 AC XY: 1048 AN XY: 130422

Gnomad AFR exome AF: 0.000571

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.0332

Gnomad SAS exome AF: 0.00243

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.00594 AC: 8623 AN: 1452696 Hom.: 51 Cov.: 35 AF XY: 0.00597 AC XY: 4317 AN XY: 723116

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.0291

Gnomad4 SAS exome AF: 0.00247

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.00500

Gnomad4 OTH exome AF: 0.00612

GnomAD4 genome AF: 0.00721 AC: 1098 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00828 AC XY: 617 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0286

Gnomad4 NFE AF: 0.00656

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00656 Hom.: 4

Bravo AF: 0.00526

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00865 AC: 1048

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 23, 2017

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.018	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.024	D;D
Vest4		0.56
MVP		0.81
MPC		0.50
ClinPred		0.013	T
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79016973; hg19: chr1-978974; COSMIC: COSV65069756; COSMIC: COSV65069756;