rs113904914

chr3-49532547-G-Achr3-49532547-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004393.6(DAG1):c.2036G>A(p.Arg679His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,462 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R679C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.977

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009759963).
• BP6: Variant 3-49532547-G-A is Benign according to our data. Variant chr3-49532547-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49532547-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAG1	NM_004393.6	c.2036G>A	p.Arg679His	missense_variant	3/3	ENST00000308775.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAG1	ENST00000308775.7	c.2036G>A	p.Arg679His	missense_variant	3/3	1	NM_004393.6	P1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152224 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000558 AC: 140 AN: 250972 Hom.: 0 AF XY: 0.000494 AC XY: 67 AN XY: 135680

Gnomad AFR exome AF: 0.00709

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000285 AC: 416 AN: 1461120 Hom.: 1 Cov.: 33 AF XY: 0.000274 AC XY: 199 AN XY: 726704

Gnomad4 AFR exome AF: 0.00849

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152342 Hom.: 3 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74488

Gnomad4 AFR AF: 0.00702

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00244

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 10, 2015

- -

DAG1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D;.;.;.;.;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0098	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L
MutationTaster	Benign	0.88	D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Benign	0.030
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D
Polyphen		0.065	B;B;B;B;B;B
Vest4		0.20
MVP		0.51
MPC		0.78
ClinPred		0.021	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.35

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: rs113904914; hg19: chr3-49569980;