dbSNP rs1188075071: MAK16:p.Thr127Lys (chr8-33489127-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032509.4(MAK16):c.380C>A(p.Thr127Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T127I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAK16
NM_032509.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.74

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

TTI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12200746).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032509.4. 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
	MAK16	NM_032509.4	MANE Select	c.380C>A	p.Thr127Lys	missense	Exon 5 of 10	NP_115898.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAK16	ENST00000360128.11	TSL:1 MANE Select	c.380C>A	p.Thr127Lys	missense	Exon 5 of 10	ENSP00000353246.5	Q9BXY0
MAK16	ENST00000520763.5	TSL:1	n.405C>A		non_coding_transcript_exon	Exon 5 of 5
MAK16	ENST00000929670.1		c.758C>A	p.Thr253Lys	missense	Exon 5 of 10	ENSP00000599729.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460206

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726518

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110906

Other (OTH)

AF:

0.00

AC:

AN:

60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0099

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.024

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.037

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.11

PhyloP100

5.7

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

1.3

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.43

MutPred

0.47

Gain of methylation at T127 (P = 0.0224)

MVP

0.11

MPC

0.21

ClinPred

0.76

GERP RS

6.0

Varity_R

0.13

gMVP

0.79

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over