16-53494145-C-T

Position:

• chr16-53494145-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022476.4(AKTIP):​c.703G>A​(p.Ala235Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,612,276 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: AKTIP NM_022476.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.77

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018119693).
• BP6: Variant 16-53494145-C-T is Benign according to our data. Variant chr16-53494145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 725925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKTIP	NM_022476.4	c.703G>A	p.Ala235Thr	missense_variant	8/10	ENST00000394657.12	NP_071921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKTIP	ENST00000394657.12	c.703G>A	p.Ala235Thr	missense_variant	8/10	2	NM_022476.4	ENSP00000378152.6
AKTIP	ENST00000570004.5	c.703G>A	p.Ala235Thr	missense_variant	8/10	1		ENSP00000455874.1
AKTIP	ENST00000300245.8	c.703G>A	p.Ala235Thr	missense_variant	9/11	5		ENSP00000300245.4

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 396 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00265 AC: 666 AN: 251434 Hom.: 2 AF XY: 0.00265 AC XY: 360 AN XY: 135896

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00430 AC: 6276 AN: 1459984 Hom.: 20 Cov.: 30 AF XY: 0.00415 AC XY: 3018 AN XY: 726424

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00320

Gnomad4 NFE exome AF: 0.00499

Gnomad4 OTH exome AF: 0.00433

GnomAD4 genome AF: 0.00260 AC: 396 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74472

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00377 Hom.: 2

Bravo AF: 0.00227

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00251 AC: 305

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Uncertain	0.084	D
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.66	P;D;P
Vest4		0.82
MVP		0.75
MPC		1.5
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs118126947; hg19: chr16-53528057; COSMIC: COSV50883015; COSMIC: COSV50883015;