22-27982396-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (112 hom., cov: 31)
  • Exomes 𝑓: 0.044 (1583 hom.)
• Consequence: TTC28 NM_001145418.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.304

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

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTC28
• 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 id is 3056496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC28	NM_001145418.2	c.7271C>G	p.Ala2424Gly	missense_variant	23/23	ENST00000397906.7
TTC28-AS1	NR_026963.1	n.251-12077G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC28	ENST00000397906.7	c.7271C>G	p.Ala2424Gly	missense_variant	23/23	1	NM_001145418.2	P1
TTC28-AS1	ENST00000454741.5	n.206-12077G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4964 AN: 152064 Hom.: 112 Cov.: 31

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

GnomAD3 exomes AF: 0.0347 AC: 5415 AN: 156262 Hom.: 132 AF XY: 0.0340 AC XY: 2817 AN XY: 82824

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 SAS exome AF: 0.0115

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.: 30 AF XY: 0.0429 AC XY: 29612 AN XY: 690128

Gnomad4 AFR exome AF: 0.00817

Gnomad4 AMR exome AF: 0.0293

Gnomad4 ASJ exome AF: 0.0738

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0298

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0423

GnomAD4 genome AF: 0.0326 AC: 4964 AN: 152182 Hom.: 112 Cov.: 31 AF XY: 0.0306 AC XY: 2279 AN XY: 74378

Gnomad4 AFR AF: 0.00824

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.0704

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00936

Gnomad4 FIN AF: 0.0280

Gnomad4 NFE AF: 0.0497

Gnomad4 OTH AF: 0.0422

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: 12

ESP6500EA AF: 0.0603 AC: 192

ExAC AF: 0.0267 AC: 709

Asia WGS AF: 0.00693 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TTC28-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.079
Dann	Benign	0.62
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	.;B
Vest4		0.024
ClinPred		0.0014	T
GERP RS		0.18
Varity_R		0.033
gMVP		0.068

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

LitVar

Other links and lift over

dbSNP: rs41278845; hg19: chr22-28378384; COSMIC: COSV67413171; COSMIC: COSV67413171;