chr10-132194911-C-G

Position:

• chr10-132194911-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006426.3(DPYSL4):​c.380C>G​(p.Ala127Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DPYSL4 NM_006426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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]

DPYSL4 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYSL4	NM_006426.3	c.380C>G	p.Ala127Gly	missense_variant	4/14	ENST00000338492.9	NP_006417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL4	ENST00000338492.9	c.380C>G	p.Ala127Gly	missense_variant	4/14	1	NM_006426.3	ENSP00000339850.3
DPYSL4	ENST00000368627.1	c.149C>G	p.Ala50Gly	missense_variant	2/10	5		ENSP00000357616.1
DPYSL4	ENST00000493882.1	n.537C>G		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460212 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726442

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 20, 2024

The c.380C>G (p.A127G) alteration is located in exon 4 (coding exon 4) of the DPYSL4 gene. This alteration results from a C to G substitution at nucleotide position 380, causing the alanine (A) at amino acid position 127 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.97	D;.
Vest4		0.74
MutPred		0.76		Loss of stability (P = 0.0378);.;
MVP		0.96
MPC		0.87
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.79

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: rs767534507; hg19: chr10-134008415;