rs41290704

Positions:

• chr3-49531110-C-G

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.599C>G​(p.Thr200Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00204 in 1,614,194 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.04

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=0.01572135).
• BP6: Variant 3-49531110-C-G is Benign according to our data. Variant chr3-49531110-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 196388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49531110-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAG1	NM_004393.6	c.599C>G	p.Thr200Ser	missense_variant	3/3	ENST00000308775.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAG1	ENST00000308775.7	c.599C>G	p.Thr200Ser	missense_variant	3/3	1	NM_004393.6	P1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00202 AC: 507 AN: 251490 Hom.: 1 AF XY: 0.00199 AC XY: 270 AN XY: 135916

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00209 AC: 3052 AN: 1461894 Hom.: 7 Cov.: 32 AF XY: 0.00200 AC XY: 1458 AN XY: 727248

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74464

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00291

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00153

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	This variant is associated with the following publications: (PMID: 24036952, 28008999) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DAG1: BS1, BS2 -

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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;T;T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;.;.;.;.;.
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.016	T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.34	T;T;T;T;T;T
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		0.91	P;P;P;P;P;P
Vest4		0.42
MutPred		0.56		Loss of glycosylation at P204 (P = 0.0497);Loss of glycosylation at P204 (P = 0.0497);Loss of glycosylation at P204 (P = 0.0497);Loss of glycosylation at P204 (P = 0.0497);Loss of glycosylation at P204 (P = 0.0497);Loss of glycosylation at P204 (P = 0.0497);
MVP		0.71
MPC		0.73
ClinPred		0.020	T
GERP RS		5.9
Varity_R		0.16
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: rs41290704; hg19: chr3-49568543;