rs79016973

Variant names:

• chr1-1043594-G-A
• rs79016973
• NM_198576.4:c.1660G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1043594-G-A
• chr1-1043594-G-T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 7.44
• Publications: 12 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 263165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.1660G>A	p.Val554Met	missense	Exon 9 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1660G>A	p.Val554Met	missense	Exon 9 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1345G>A	p.Val449Met	missense	Exon 8 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1660G>A	p.Val554Met	missense	Exon 9 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1345G>A	p.Val449Met	missense	Exon 8 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1345G>A	p.Val449Met	missense	Exon 8 of 35	ENSP00000498543.1

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

GnomAD2 exomes AF: 0.00811 AC: 1933 AN: 238454 AF XY: 0.00804

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33464

American (AMR) AF: 0.00168 AC: 75 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26100

East Asian (EAS) AF: 0.0291 AC: 1155 AN: 39688

South Asian (SAS) AF: 0.00247 AC: 213 AN: 86228

European-Finnish (FIN) AF: 0.0261 AC: 1167 AN: 44682

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00500 AC: 5562 AN: 1111754

Other (OTH) AF: 0.00612 AC: 369 AN: 60318

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

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.00595 AC: 91 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5184

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4830

European-Finnish (FIN) AF: 0.0286 AC: 304 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00656 AC: 446 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00658 Hom.: 13

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
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
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs79016973; hg19: chr1-978974; COSMIC: COSV65069756; COSMIC: COSV65069756;