19-45770541-C-T

Variant names:

• chr19-45770541-C-T
• rs1003871860
• NM_004409.5:c.1837G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004409.5(DMPK):​c.1837G>A​(p.Ala613Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A613S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DMPK NM_004409.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480
• Publications: 0 publications found

Genes affected

DMPK (HGNC:2933): (DM1 protein kinase) The protein encoded by this gene is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. The 3' untranslated region of this gene contains 5-38 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2016]

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09217781).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004409.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMPK	NM_004409.5	MANE Select	c.1837G>A	p.Ala613Thr	missense	Exon 15 of 15	NP_004400.4
	DMPK	NM_001288764.2		c.1915G>A	p.Ala639Thr	missense	Exon 16 of 16	NP_001275693.1
	DMPK	NM_001081563.3		c.1867G>A	p.Ala623Thr	missense	Exon 14 of 14	NP_001075032.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMPK	ENST00000291270.9	TSL:5 MANE Select	c.1837G>A	p.Ala613Thr	missense	Exon 15 of 15	ENSP00000291270.4
	DMPK	ENST00000447742.6	TSL:1	c.1822G>A	p.Ala608Thr	missense	Exon 15 of 15	ENSP00000413417.1
	DMPK	ENST00000343373.10	TSL:1	c.1833G>A	p.Thr611Thr	synonymous	Exon 15 of 15	ENSP00000345997.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.048
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.014
Sift	Benign	0.15	T
Sift4G	Benign	0.27	T
Polyphen		0.026	B
Vest4		0.12
MutPred		0.37		Loss of helix (P = 0.0558)
MVP		0.57
MPC		0.34
ClinPred		0.11	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.18
Mutation Taster		=100/0	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: rs1003871860; hg19: chr19-46273799;