1-156581582-G-A

Position:

• chr1-156581582-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105669.4(TTC24):​c.218G>A​(p.Arg73Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TTC24 NM_001105669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.568

Genes affected

TTC24 (HGNC:32348): (tetratricopeptide repeat domain 24)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07854101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC24	NM_001105669.4	c.218G>A	p.Arg73Lys	missense_variant	2/11	ENST00000368236.8	NP_001099139.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC24	ENST00000368236.8	c.218G>A	p.Arg73Lys	missense_variant	2/11	5	NM_001105669.4	ENSP00000357219	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 AF XY: 0.0000247 AC XY: 2 AN XY: 80962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399328 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 690172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 23, 2021

The c.218G>A (p.R73K) alteration is located in exon 2 (coding exon 1) of the TTC24 gene. This alteration results from a G to A substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a lysine (K). 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	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.7
DANN	Benign	0.67
DEOGEN2	Benign	0.00060	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.34	T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.061
Sift	Benign	0.36	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.039
MutPred		0.46		Gain of ubiquitination at R73 (P = 0.0146);Gain of ubiquitination at R73 (P = 0.0146);
MVP		0.22
MPC		0.097
ClinPred		0.054	T
GERP RS		0.17
Varity_R		0.045
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1254229471; hg19: chr1-156551374;