10-132192790-C-A

Variant names:

• chr10-132192790-C-A
• rs147309993
• NM_006426.3:c.261C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006426.3(DPYSL4):​c.261C>A​(p.Asp87Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,646 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: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DPYSL4 NM_006426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL4	NM_006426.3	c.261C>A	p.Asp87Glu	missense_variant	Exon 3 of 14	ENST00000338492.9	NP_006417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL4	ENST00000338492.9	c.261C>A	p.Asp87Glu	missense_variant	Exon 3 of 14	1	NM_006426.3	ENSP00000339850.3
DPYSL4	ENST00000368627.1	c.30C>A	p.Asp10Glu	missense_variant	Exon 1 of 10	5		ENSP00000357616.1
DPYSL4	ENST00000493882.1	n.418C>A		non_coding_transcript_exon_variant	Exon 4 of 6	3
DPYSL4	ENST00000493927.5	n.585C>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460646 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726610

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.261C>A (p.D87E) alteration is located in exon 3 (coding exon 3) of the DPYSL4 gene. This alteration results from a C to A substitution at nucleotide position 261, causing the aspartic acid (D) at amino acid position 87 to be replaced by a glutamic acid (E). 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	0.68
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	0.068
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.063	T;D
Sift4G	Benign	0.078	T;T
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.81		Gain of helix (P = 0.1736);.;
MVP		0.73
MPC		0.93
ClinPred		0.96	D
GERP RS		-9.6
Varity_R		0.72
gMVP		0.90

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: rs147309993; hg19: chr10-134006294;