19-32439893-A-G

Variant names:

• chr19-32439893-A-G
• rs746399509
• NM_001172774.2:c.838A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001172774.2(DPY19L3):​c.838A>G​(p.Met280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DPY19L3 NM_001172774.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

DPY19L3 (HGNC:27120): (dpy-19 like C-mannosyltransferase 3) Predicted to enable mannosyltransferase activity. Predicted to be involved in protein C-linked glycosylation via 2'-alpha-mannosyl-L-tryptophan. Predicted to be integral component of membrane. Predicted to be active in nuclear inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13467285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPY19L3	NM_001172774.2	c.838A>G	p.Met280Val	missense_variant	Exon 8 of 19	ENST00000392250.7	NP_001166245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPY19L3	ENST00000392250.7	c.838A>G	p.Met280Val	missense_variant	Exon 8 of 19	5	NM_001172774.2	ENSP00000376081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250184 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461032 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726798

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.838A>G (p.M280V) alteration is located in exon 8 (coding exon 7) of the DPY19L3 gene. This alteration results from a A to G substitution at nucleotide position 838, causing the methionine (M) at amino acid position 280 to be replaced by a valine (V). 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	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0045
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T;T;.
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.65	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.25	T;.;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.40
MutPred		0.57		Gain of ubiquitination at K285 (P = 0.0837);Gain of ubiquitination at K285 (P = 0.0837);Gain of ubiquitination at K285 (P = 0.0837);
MVP		0.30
MPC		0.28
ClinPred		0.11	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.34

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: rs746399509; hg19: chr19-32930799;