NM_004393.6:c.1306A>G

Variant names:

• chr3-49531817-A-G
• rs149838438
• NM_004393.6:c.1306A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004393.6(DAG1):​c.1306A>G​(p.Thr436Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T436M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.29
• Publications: 2 publications found

Genes affected

DAG1 (HGNC:2666): (dystroglycan 1) This gene encodes dystroglycan, a central component of dystrophin-glycoprotein complex that links the extracellular matrix and the cytoskeleton in the skeletal muscle. The encoded preproprotein undergoes O- and N-glycosylation, and proteolytic processing to generate alpha and beta subunits. Certain mutations in this gene are known to cause distinct forms of muscular dystrophy. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Nov 2015]

DAG1 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2P

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• isolated asymptomatic elevation of creatine phosphokinase

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1115343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004393.6. 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
	DAG1	NM_004393.6	MANE Select	c.1306A>G	p.Thr436Ala	missense	Exon 3 of 3	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.1306A>G	p.Thr436Ala	missense	Exon 6 of 6	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.1306A>G	p.Thr436Ala	missense	Exon 6 of 6	NP_001171105.2	Q14118

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.1306A>G	p.Thr436Ala	missense	Exon 3 of 3	ENSP00000312435.2	Q14118
	DAG1	ENST00000418588.6	TSL:3	c.1306A>G	p.Thr436Ala	missense	Exon 4 of 4	ENSP00000405859.2	Q14118
	DAG1	ENST00000421560.6	TSL:4	c.1306A>G	p.Thr436Ala	missense	Exon 3 of 3	ENSP00000412067.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.0000858 AC: 13 AN: 151514 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251462 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.000132 AC XY: 96 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1112010

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.0000857 AC: 13 AN: 151632 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74102

African (AFR) AF: 0.0000242 AC: 1 AN: 41318

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000247 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.0098
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.051
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.18	B
Vest4		0.17
MVP		0.50
MPC		0.28
ClinPred		0.088	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.44
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs149838438; hg19: chr3-49569250; COSMIC: COSV58188195; COSMIC: COSV58188195;