rs145403829

chr3-49510792-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004393.6(DAG1):c.258G>C(p.Leu86Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,614,192 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.02

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010102391).
• BP6: Variant 3-49510792-G-C is Benign according to our data. Variant chr3-49510792-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195220.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=2}. Variant chr3-49510792-G-C 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.258G>C	p.Leu86Phe	missense_variant	2/3	ENST00000308775.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAG1	ENST00000308775.7	c.258G>C	p.Leu86Phe	missense_variant	2/3	1	NM_004393.6	P1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152202 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00508

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00289 AC: 725 AN: 251042 Hom.: 0 AF XY: 0.00290 AC XY: 393 AN XY: 135660

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00474 AC: 6932 AN: 1461872 Hom.: 22 Cov.: 75 AF XY: 0.00467 AC XY: 3398 AN XY: 727234

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00559

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152320 Hom.: 2 Cov.: 31 AF XY: 0.00293 AC XY: 218 AN XY: 74474

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00449 Hom.: 8

Bravo AF: 0.00341

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DAG1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 26, 2015	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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 26, 2024

- -

DAG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T;T;T;T;T;T;T;.;.;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.73	T;T;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0061	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.0	L;.;L;L;L;L;L;.;.;.;.
MutationTaster	Benign	0.79	D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;D;T;T;T;T;T;D;D;D;D
Polyphen		0.0010	B;.;B;B;B;B;B;.;.;.;.
Vest4		0.15
MutPred		0.72		Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);
MVP		0.60
MPC		0.30
ClinPred		0.0050	T
GERP RS		4.3
Varity_R		0.038
gMVP		0.51

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: rs145403829; hg19: chr3-49548225; COSMIC: COSV99067795; COSMIC: COSV99067795;