4-99840363-C-T

Position:

• chr4-99840363-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014395.3(DAPP1):​c.299C>T​(p.Ser100Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DAPP1 NM_014395.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28

Genes affected

DAPP1 (HGNC:16500): (dual adaptor of phosphotyrosine and 3-phosphoinositides 1) Enables phosphatidylinositol-3,4,5-trisphosphate binding activity and phosphatidylinositol-3,4-bisphosphate binding activity. Predicted to be involved in signal transduction. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

DAPP1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.361978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAPP1	NM_014395.3	c.299C>T	p.Ser100Leu	missense_variant	3/9	ENST00000512369.2	NP_055210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAPP1	ENST00000512369.2	c.299C>T	p.Ser100Leu	missense_variant	3/9	1	NM_014395.3	ENSP00000423602.1
DAPP1	ENST00000296414.11	c.299C>T	p.Ser100Leu	missense_variant	3/10	1		ENSP00000296414.7
DAPP1	ENST00000507994.1	n.363C>T		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458808 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725594

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: 0.00

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

Oct 08, 2024

The c.299C>T (p.S100L) alteration is located in exon 3 (coding exon 3) of the DAPP1 gene. This alteration results from a C to T substitution at nucleotide position 299, causing the serine (S) at amino acid position 100 to be replaced by a leucine (L). 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	0.067
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	-0.0010	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.32
Sift	Benign	0.30	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	.;B
Vest4		0.30
MutPred		0.56		Gain of glycosylation at S101 (P = 0.0746);Gain of glycosylation at S101 (P = 0.0746);
MVP		0.93
MPC		0.51
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1723454277; hg19: chr4-100761520;