chr3-57227919-G-C

Variant names:

• chr3-57227919-G-C
• rs79282761
• NM_012096.3:c.36G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_012096.3(APPL1):​c.36G>C​(p.Thr12Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,464,962 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (145 hom.)
• Consequence: APPL1 NM_012096.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.265
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-57227919-G-C is Benign according to our data. Variant chr3-57227919-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1183160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.265 with no splicing effect.
• BS2: High AC in GnomAd4 at 1337 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.36G>C	p.Thr12Thr	synonymous	Exon 1 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.36G>C	p.Thr12Thr	synonymous	Exon 1 of 22	ENSP00000288266.3	Q9UKG1
	APPL1	ENST00000482800.5	TSL:1	n.131G>C		non_coding_transcript_exon	Exon 1 of 20
	APPL1	ENST00000855520.1		c.36G>C	p.Thr12Thr	synonymous	Exon 1 of 23	ENSP00000525579.1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1337 AN: 151984 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00890

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00827 AC: 794 AN: 96026 AF XY: 0.00789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000211

Gnomad ASJ exome AF: 0.00304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00489 AC: 6415 AN: 1312870 Hom.: 145 Cov.: 30 AF XY: 0.00508 AC XY: 3287 AN XY: 647444

African (AFR) AF: 0.0000373 AC: 1 AN: 26788

American (AMR) AF: 0.000169 AC: 5 AN: 29600

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 72 AN: 22744

East Asian (EAS) AF: 0.00 AC: 0 AN: 28680

South Asian (SAS) AF: 0.00132 AC: 95 AN: 72128

European-Finnish (FIN) AF: 0.0661 AC: 2586 AN: 39120

Middle Eastern (MID) AF: 0.00238 AC: 9 AN: 3778

European-Non Finnish (NFE) AF: 0.00330 AC: 3415 AN: 1036346

Other (OTH) AF: 0.00432 AC: 232 AN: 53686

GnomAD4 genome AF: 0.00879 AC: 1337 AN: 152092 Hom.: 38 Cov.: 33 AF XY: 0.0107 AC XY: 797 AN XY: 74368

African (AFR) AF: 0.000265 AC: 11 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0657 AC: 691 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00890 AC: 605 AN: 67960

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.0108 Hom.: 13

Bravo AF: 0.00270

Asia WGS AF: 0.00147 AC: 6 AN: 3424

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.9
DANN	Benign	0.83
PhyloP100		0.27
PromoterAI		0.063	Neutral
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: rs79282761; hg19: chr3-57261947;