11-113323374-G-A

Variant names:

• chr11-113323374-G-A
• NM_017868.4:c.145G>A

Variant summary

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

The NM_017868.4(TTC12):​c.145G>A​(p.Glu49Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

Genes affected

TTC12 (HGNC:23700): (tetratricopeptide repeat domain 12) Involved in axonemal dynein complex assembly and sperm axoneme assembly. Located in centrosome and cytoplasm. Implicated in primary ciliary dyskinesia 45. [provided by Alliance of Genome Resources, Apr 2022]

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=0.1279766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 22	ENST00000529221.6	NP_060338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC12	ENST00000529221.6	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 22	2	NM_017868.4	ENSP00000433757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461242 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145G>A (p.E49K) alteration is located in exon 3 (coding exon 2) of the TTC12 gene. This alteration results from a G to A substitution at nucleotide position 145, causing the glutamic acid (E) at amino acid position 49 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	0.088
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;T;.;.;.;T;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.46	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.42	T;D;T;D;T;T;T;T;T;T
Sift4G	Benign	0.074	T;T;T;T;T;T;T;T;T;T
Polyphen		0.68	P;.;.;.;.;.;.;.;.;.
Vest4		0.12
MutPred		0.32		Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);.;Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);Gain of ubiquitination at E49 (P = 0.0011);
MVP		0.52
MPC		0.081
ClinPred		0.40	T
GERP RS		3.4
Varity_R		0.055
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-113194096;