NM_012096.3:c.256T>C

Variant names:

• chr3-57238087-T-C
• rs147166062
• NM_012096.3:c.256T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_012096.3(APPL1):​c.256T>C​(p.Leu86Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,611,706 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (40 hom.)
• Consequence: APPL1 NM_012096.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.982
• Publications: 3 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), Genomics England PanelApp, Ambry Genetics
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-57238087-T-C is Benign according to our data. Variant chr3-57238087-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 713805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.982 with no splicing effect.
• BS2: High AC in GnomAd4 at 722 AD,Unknown gene.

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.256T>C	p.Leu86Leu	synonymous	Exon 4 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.256T>C	p.Leu86Leu	synonymous	Exon 4 of 22	ENSP00000288266.3	Q9UKG1
	APPL1	ENST00000482800.5	TSL:1	n.351T>C		non_coding_transcript_exon	Exon 4 of 20
	APPL1	ENST00000855520.1		c.256T>C	p.Leu86Leu	synonymous	Exon 4 of 23	ENSP00000525579.1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00572 AC: 1426 AN: 249424 AF XY: 0.00558

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00647

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00526

GnomAD4 exome AF: 0.00565 AC: 8242 AN: 1459386 Hom.: 40 Cov.: 29 AF XY: 0.00544 AC XY: 3949 AN XY: 725798

African (AFR) AF: 0.000779 AC: 26 AN: 33392

American (AMR) AF: 0.00110 AC: 49 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 151 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00149 AC: 127 AN: 85348

European-Finnish (FIN) AF: 0.0143 AC: 764 AN: 53362

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5686

European-Non Finnish (NFE) AF: 0.00612 AC: 6799 AN: 1111174

Other (OTH) AF: 0.00524 AC: 316 AN: 60284

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74480

African (AFR) AF: 0.000938 AC: 39 AN: 41578

American (AMR) AF: 0.00419 AC: 64 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00631 AC: 429 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00529 Hom.: 2

Bravo AF: 0.00363

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00581

EpiControl AF: 0.00564

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Maturity-onset diabetes of the young type 14 (2)
-	-	2	not specified (2)
-	-	1	APPL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.4
DANN	Benign	0.80
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism

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

dbSNP: rs147166062; hg19: chr3-57272115;