NM_012096.3:c.117G>C

Variant names:

• chr3-57235628-G-C
• NM_012096.3:c.117G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012096.3(APPL1):​c.117G>C​(p.Gln39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APPL1 NM_012096.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0420
• Publications: 0 publications found

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]

APPL1 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 14

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.257244).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012096.3. 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
	APPL1	NM_012096.3	MANE Select	c.117G>C	p.Gln39His	missense	Exon 2 of 22	NP_036228.1	Q9UKG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL1	ENST00000288266.8	TSL:1 MANE Select	c.117G>C	p.Gln39His	missense	Exon 2 of 22	ENSP00000288266.3	Q9UKG1
	APPL1	ENST00000482800.5	TSL:1	n.212G>C		non_coding_transcript_exon	Exon 2 of 20
	APPL1	ENST00000855520.1		c.117G>C	p.Gln39His	missense	Exon 2 of 23	ENSP00000525579.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461250 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111632

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.042
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.34		Gain of glycosylation at Y36 (P = 0.0184)
MVP		0.65
MPC		0.29
ClinPred		0.98	D
GERP RS		-6.4
Varity_R		0.76
gMVP		0.49
Mutation Taster		=41/59	disease causing

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

Other links and lift over

hg19: chr3-57269656;