Genetic Variant TTC28:p.Ala2456Ser (chr22-27982301-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145418.2(TTC28):c.7366G>T(p.Ala2456Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A2456V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TTC28
NM_001145418.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.24

Publications

0 publications found

Variant links:

Genes affected

TTC28 (HGNC:29179): (tetratricopeptide repeat domain 28) Enables kinase binding activity. Involved in regulation of mitotic cell cycle. Located in midbody. [provided by Alliance of Genome Resources, Apr 2022]

TTC28 links:

TTC28-AS1 (HGNC:29336): (TTC28 antisense RNA 1)

TTC28-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035998046).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145418.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC28	NM_001145418.2	MANE Select	c.7366G>T	p.Ala2456Ser	missense	Exon 23 of 23	NP_001138890.1	Q96AY4
TTC28	NM_001393403.1		c.7342G>T	p.Ala2448Ser	missense	Exon 22 of 22	NP_001380332.1
TTC28	NM_001393404.1		c.7012G>T	p.Ala2338Ser	missense	Exon 22 of 22	NP_001380333.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC28	ENST00000397906.7	TSL:1 MANE Select	c.7366G>T	p.Ala2456Ser	missense	Exon 23 of 23	ENSP00000381003.2	Q96AY4
TTC28-AS1	ENST00000419253.1	TSL:1	n.146-3391C>A		intron	N/A
TTC28-AS1	ENST00000454741.5	TSL:1	n.206-12172C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.32e-7

AC:

AN:

1366530

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30414

American (AMR)

AF:

0.00

AC:

AN:

31202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22400

East Asian (EAS)

AF:

0.00

AC:

AN:

35484

South Asian (SAS)

AF:

0.00

AC:

AN:

73810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

9.41e-7

AC:

AN:

1063192

Other (OTH)

AF:

0.00

AC:

AN:

56504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.0030

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.010

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.90

PhyloP100

-1.2

PrimateAI

Benign

0.37

PROVEAN

Benign

0.020

REVEL

Benign

0.24

Sift

Benign

0.44

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.082

MutPred

0.068

Gain of glycosylation at A2456 (P = 0.0045)

MVP

0.10

ClinPred

0.060

GERP RS

-10

Varity_R

0.026

gMVP

0.059

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over