NM_006426.3:c.539A>G

Variant names:

• chr10-132196921-A-G
• NM_006426.3:c.539A>G

Variant summary

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

The NM_006426.3(DPYSL4):​c.539A>G​(p.Gln180Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DPYSL4 NM_006426.3 missense, splice_region
• Scores: Splicing: ADA: 0.9906
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07
• Publications: 0 publications found

Genes affected

DPYSL4 (HGNC:3016): (dihydropyrimidinase like 4) Enables filamin binding activity. Predicted to be involved in nervous system development. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006426.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL4	NM_006426.3	MANE Select	c.539A>G	p.Gln180Arg	missense splice_region	Exon 5 of 14	NP_006417.2	O14531

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL4	ENST00000338492.9	TSL:1 MANE Select	c.539A>G	p.Gln180Arg	missense splice_region	Exon 5 of 14	ENSP00000339850.3	O14531
	DPYSL4	ENST00000905073.1		c.539A>G	p.Gln180Arg	missense splice_region	Exon 5 of 14	ENSP00000575132.1
	DPYSL4	ENST00000905072.1		c.539A>G	p.Gln180Arg	missense splice_region	Exon 5 of 14	ENSP00000575131.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.67
MutPred		0.66		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.97
MPC		0.33
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.65
gMVP		0.76
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
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

hg19: chr10-134010425;