Genetic Variant TTC28:p.Ala2456Thr (chr22-27982301-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001145418.2(TTC28):c.7366G>A(p.Ala2456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000725 in 1,517,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

TTC28
NM_001145418.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031035215).

BP6

Variant 22-27982301-C-T is Benign according to our data. Variant chr22-27982301-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2381949.Status of the report is criteria_provided_single_submitter, 1 stars.

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>A	p.Ala2456Thr	missense	Exon 23 of 23	NP_001138890.1	Q96AY4
TTC28	NM_001393403.1		c.7342G>A	p.Ala2448Thr	missense	Exon 22 of 22	NP_001380332.1
TTC28	NM_001393404.1		c.7012G>A	p.Ala2338Thr	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>A	p.Ala2456Thr	missense	Exon 23 of 23	ENSP00000381003.2	Q96AY4
TTC28-AS1	ENST00000419253.1	TSL:1	n.146-3391C>T		intron	N/A
TTC28-AS1	ENST00000454741.5	TSL:1	n.206-12172C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000157

AC:

AN:

127672

AF XY:

0.0000300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000585

AC:

AN:

1366530

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

671022

show subpopulations

African (AFR)

AF:

0.0000658

AC:

AN:

30414

American (AMR)

AF:

0.00

AC:

AN:

31202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22400

East Asian (EAS)

AF:

0.0000282

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:

0.00000470

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

AF:

0.0000198

AC:

AN:

151412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73850

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41188

American (AMR)

AF:

0.0000661

AC:

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.012

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.014

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.48

M_CAP

Benign

0.053

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.20

PhyloP100

-1.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.29

REVEL

Benign

0.21

Sift

Benign

0.64

Sift4G

Benign

0.22

Polyphen

0.0

Vest4

0.021

MutPred

0.092

Gain of glycosylation at A2456 (P = 0.0028)

MVP

0.085

ClinPred

0.050

GERP RS

-10

Varity_R

0.017

gMVP

0.097

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over