Variant 8-33498615-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000360128.11(MAK16):c.889G>A(p.Ala297Thr) 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 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAK16
ENST00000360128.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

Variant links:

Genes affected

MAK16 (HGNC:13703): (MAK16 homolog) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

MAK16 links:

TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

TTI2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036320508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAK16	NM_032509.4 linkuse as main transcript	c.889G>A	p.Ala297Thr	missense_variant	10/10	ENST00000360128.11	NP_115898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAK16	ENST00000360128.11 linkuse as main transcript	c.889G>A	p.Ala297Thr	missense_variant	10/10	1	NM_032509.4	ENSP00000353246	P1
TTI2	ENST00000613904.1 linkuse as main transcript	c.*558C>T		3_prime_UTR_variant	8/8	1		ENSP00000478396	P1
MAK16	ENST00000518389.1 linkuse as main transcript	c.*429G>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	5		ENSP00000430403
TTI2	ENST00000519356.1 linkuse as main transcript	n.628+1713C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.889G>A (p.A297T) alteration is located in exon 10 (coding exon 10) of the MAK16 gene. This alteration results from a G to A substitution at nucleotide position 889, causing the alanine (A) at amino acid position 297 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.67

M_CAP

Benign

0.0036

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.93

PrimateAI

Benign

0.29

PROVEAN

Benign

0.010

REVEL

Benign

0.098

Sift

Benign

0.51

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.056

MutPred

0.089

Gain of relative solvent accessibility (P = 0.005);

MVP

0.14

MPC

0.17

ClinPred

0.13

GERP RS

0.95

Varity_R

0.027

gMVP

0.059

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over