19-45785871-C-T

Position:

• chr19-45785871-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004943.2(DMWD):​c.1625G>A​(p.Arg542His) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DMWD NM_004943.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

Genes affected

DMWD (HGNC:2936): (DM1 locus, WD repeat containing) Predicted to be located in dendrite; nucleus; and perikaryon. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000268434 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMWD	NM_004943.2	c.1625G>A	p.Arg542His	missense_variant	3/5	ENST00000270223.7	NP_004934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMWD	ENST00000270223.7	c.1625G>A	p.Arg542His	missense_variant	3/5	1	NM_004943.2	ENSP00000270223.5
DMWD	ENST00000377735.7	c.1625G>A	p.Arg542His	missense_variant	3/4	5		ENSP00000366964.3
DMWD	ENST00000602829.1	c.38G>A	p.Arg13His	missense_variant	1/1	6		ENSP00000473377.1
ENSG00000268434	ENST00000593999.1	n.101G>A		non_coding_transcript_exon_variant	1/3	2		ENSP00000471312.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454404 Hom.: 0 Cov.: 78 AF XY: 0.00000276 AC XY: 2 AN XY: 723832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.1625G>A (p.R542H) alteration is located in exon 3 (coding exon 3) of the DMWD gene. This alteration results from a G to A substitution at nucleotide position 1625, causing the arginine (R) at amino acid position 542 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.026	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.036	D;D
Sift4G	Benign	0.090	T;T
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.40		Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);
MVP		0.99
MPC		2.1
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.39
gMVP		0.56

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: rs1192659698; hg19: chr19-46289129;