16-53494605-G-A

Variant names:

• chr16-53494605-G-A
• rs781311887
• NM_022476.4:c.415C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_022476.4(AKTIP):​c.415C>T​(p.Arg139Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000335 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: AKTIP NM_022476.4 missense, splice_region
• Scores: Splicing: ADA: 0.9919
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87
• Publications: 2 publications found

Genes affected

AKTIP (HGNC:16710): (AKT interacting protein) The mouse homolog of this gene produces fused toes and thymic hyperplasia in heterozygous mutant animals while homozygous mutants die in early development. This gene may play a role in apoptosis as these morphological abnormalities are caused by altered patterns of programmed cell death. The protein encoded by this gene is similar to the ubiquitin ligase domain of other ubiquitin-conjugating enzymes but lacks the conserved cysteine residue that enables those enzymes to conjugate ubiquitin to the target protein. This protein interacts directly with serine/threonine kinase protein kinase B (PKB)/Akt and modulates PKB activity by enhancing the phosphorylation of PKB's regulatory sites. Alternative splicing results in two transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022476.4. 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
	AKTIP	NM_022476.4	MANE Select	c.415C>T	p.Arg139Cys	missense splice_region	Exon 6 of 10	NP_071921.1	Q9H8T0-1
	AKTIP	NM_001308325.2		c.415C>T	p.Arg139Cys	missense splice_region	Exon 6 of 10	NP_001295254.1	Q9H8T0-2
	AKTIP	NM_001012398.3		c.415C>T	p.Arg139Cys	missense splice_region	Exon 6 of 10	NP_001012398.1	Q9H8T0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKTIP	ENST00000394657.12	TSL:2 MANE Select	c.415C>T	p.Arg139Cys	missense splice_region	Exon 6 of 10	ENSP00000378152.6	Q9H8T0-1
	AKTIP	ENST00000570004.5	TSL:1	c.415C>T	p.Arg139Cys	missense splice_region	Exon 6 of 10	ENSP00000455874.1	Q9H8T0-1
	AKTIP	ENST00000895076.1		c.544C>T	p.Arg182Cys	missense splice_region	Exon 7 of 11	ENSP00000565135.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250582 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461294 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726950

African (AFR) AF: 0.0000897 AC: 3 AN: 33444

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111638

Other (OTH) AF: 0.0000497 AC: 3 AN: 60360

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.65
MPC		0.84
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.67
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.14		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: rs781311887; hg19: chr16-53528517; COSMIC: COSV50886811; COSMIC: COSV50886811;