NM_012096.3:c.214C>A

Variant names:

• chr3-57238045-C-A
• rs201654453
• NM_012096.3:c.214C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012096.3(APPL1):​c.214C>A​(p.Arg72Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000055 in 1,454,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: APPL1 NM_012096.3 missense, splice_region
• Scores: Splicing: ADA: 0.4916
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62

Genes affected

APPL1 (HGNC:24035): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18974349).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL1	NM_012096.3	c.214C>A	p.Arg72Ser	missense_variant, splice_region_variant	Exon 4 of 22	ENST00000288266.8	NP_036228.1
APPL1	XM_011533583.4	c.163C>A	p.Arg55Ser	missense_variant, splice_region_variant	Exon 5 of 23		XP_011531885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL1	ENST00000288266.8	c.214C>A	p.Arg72Ser	missense_variant, splice_region_variant	Exon 4 of 22	1	NM_012096.3	ENSP00000288266.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454488 Hom.: 0 Cov.: 29 AF XY: 0.00000830 AC XY: 6 AN XY: 723248

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: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.14
Sift	Benign	0.13	T;T
Sift4G	Benign	0.10	T;D
Polyphen		0.077	B;B
Vest4		0.85
MutPred		0.36		Gain of disorder (P = 0.0506);.;
MVP		0.71
MPC		0.24
ClinPred		0.81	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.010		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: rs201654453; hg19: chr3-57272073;