22-27982348-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001145418.2(TTC28):c.7319C>T(p.Ser2440Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,394,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: TTC28 NM_001145418.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.913

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TTC28
• BP4: Computational evidence support a benign effect (MetaRNN=0.09394246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC28	NM_001145418.2	c.7319C>T	p.Ser2440Leu	missense_variant	23/23	ENST00000397906.7
TTC28-AS1	NR_026963.1	n.251-12125G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC28	ENST00000397906.7	c.7319C>T	p.Ser2440Leu	missense_variant	23/23	1	NM_001145418.2	P1
TTC28-AS1	ENST00000454741.5	n.206-12125G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1394662 Hom.: 0 Cov.: 30 AF XY: 0.0000247 AC XY: 17 AN XY: 687476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000260

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.7319C>T (p.S2440L) alteration is located in exon 23 (coding exon 23) of the TTC28 gene. This alteration results from a C to T substitution at nucleotide position 7319, causing the serine (S) at amino acid position 2440 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.21	T;T
Polyphen		0.0010	.;B
Vest4		0.10
MVP		0.34
ClinPred		0.048	T
GERP RS		3.0
Varity_R		0.034
gMVP		0.13

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: rs887416829; hg19: chr22-28378336;