Genetic Variant TTC28:p.Ala2424Gly (chr22-27982396-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001145418.2(TTC28):c.7271C>G(p.Ala2424Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,551,410 control chromosomes in the GnomAD database, including 1,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.033 ( 112 hom., cov: 31)

Exomes 𝑓: 0.044 ( 1583 hom. )

Consequence

TTC28
NM_001145418.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.304

Publications

8 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021651983).

BP6

Variant 22-27982396-G-C is Benign according to our data. Variant chr22-27982396-G-C is described in ClinVar as Benign. ClinVar VariationId is 3056496.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

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.7271C>G	p.Ala2424Gly	missense	Exon 23 of 23	NP_001138890.1	Q96AY4
TTC28	NM_001393403.1		c.7247C>G	p.Ala2416Gly	missense	Exon 22 of 22	NP_001380332.1
TTC28	NM_001393404.1		c.6917C>G	p.Ala2306Gly	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.7271C>G	p.Ala2424Gly	missense	Exon 23 of 23	ENSP00000381003.2	Q96AY4
TTC28-AS1	ENST00000419253.1	TSL:1	n.146-3296G>C		intron	N/A
TTC28-AS1	ENST00000454741.5	TSL:1	n.206-12077G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4964

AN:

152064

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00828

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0340

Gnomad ASJ

AF:

0.0704

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00894

Gnomad FIN

AF:

0.0280

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0497

Gnomad OTH

AF:

0.0426

GnomAD2 exomes

AF:

0.0347

AC:

5415

AN:

156262

AF XY:

0.0340

show subpopulations

Gnomad AFR exome

AF:

0.00758

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0753

Gnomad EAS exome

AF:

0.000183

Gnomad FIN exome

AF:

0.0295

Gnomad NFE exome

AF:

0.0507

Gnomad OTH exome

AF:

0.0452

GnomAD4 exome

AF:

0.0439

AC:

61405

AN:

1399228

Hom.:

1583

Cov.:

AF XY:

0.0429

AC XY:

29612

AN XY:

690128

show subpopulations

African (AFR)

AF:

0.00817

AC:

258

AN:

31598

American (AMR)

AF:

0.0293

AC:

1047

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0738

AC:

1858

AN:

25172

East Asian (EAS)

AF:

0.000112

AC:

AN:

35738

South Asian (SAS)

AF:

0.0106

AC:

838

AN:

79236

European-Finnish (FIN)

AF:

0.0298

AC:

1462

AN:

49122

Middle Eastern (MID)

AF:

0.0784

AC:

447

AN:

5698

European-Non Finnish (NFE)

AF:

0.0492

AC:

53035

AN:

1078960

Other (OTH)

AF:

0.0423

AC:

2456

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3635

7271

10906

14542

18177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2004

4008

6012

8016

10020

<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:

0.0326

AC:

4964

AN:

152182

Hom.:

112

Cov.:

AF XY:

0.0306

AC XY:

2279

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00824

AC:

342

AN:

41530

American (AMR)

AF:

0.0340

AC:

520

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0704

AC:

244

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00936

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0280

AC:

297

AN:

10612

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0497

AC:

3382

AN:

67988

Other (OTH)

AF:

0.0422

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

240

480

721

961

1201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0469

Hom.:

150

Bravo

AF:

0.0340

TwinsUK

AF:

0.0558

AC:

207

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.00867

AC:

ESP6500EA

AF:

0.0603

AC:

192

ExAC

AF:

0.0267

AC:

709

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TTC28-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.079

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.013

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.90

PhyloP100

0.30

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.32

REVEL

Benign

0.13

Sift

Benign

0.45

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.024

ClinPred

0.0014

GERP RS

0.18

Varity_R

0.033

gMVP

0.068

Mutation Taster

=99/1

polymorphism (auto)

(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