chr19-45786179-C-G

Variant names:

• chr19-45786179-C-G
• rs759194755
• NM_004943.2:c.1317G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004943.2(DMWD):​c.1317G>C​(p.Gln439His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DMWD NM_004943.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMWD	NM_004943.2	c.1317G>C	p.Gln439His	missense_variant	Exon 3 of 5	ENST00000270223.7	NP_004934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMWD	ENST00000270223.7	c.1317G>C	p.Gln439His	missense_variant	Exon 3 of 5	1	NM_004943.2	ENSP00000270223.5
DMWD	ENST00000377735.7	c.1317G>C	p.Gln439His	missense_variant	Exon 3 of 4	5		ENSP00000366964.3
ENSG00000268434	ENST00000593999.1	n.-208G>C		upstream_gene_variant		2		ENSP00000471312.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1317G>C (p.Q439H) alteration is located in exon 3 (coding exon 3) of the DMWD gene. This alteration results from a G to C substitution at nucleotide position 1317, causing the glutamine (Q) at amino acid position 439 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	0.85
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		3.2
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.79
MutPred		0.55		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.66
MPC		1.7
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.77
Mutation Taster		=67/33	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: rs759194755; hg19: chr19-46289437;