11-113324625-G-A

Variant names:

• chr11-113324625-G-A
• rs782193998
• NM_017868.4:c.265G>A

Variant summary

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

The NM_017868.4(TTC12):​c.265G>A​(p.Glu89Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4	c.265G>A	p.Glu89Lys	missense_variant	Exon 5 of 22	ENST00000529221.6	NP_060338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC12	ENST00000529221.6	c.265G>A	p.Glu89Lys	missense_variant	Exon 5 of 22	2	NM_017868.4	ENSP00000433757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251180 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>A (p.E89K) alteration is located in exon 5 (coding exon 4) of the TTC12 gene. This alteration results from a G to A substitution at nucleotide position 265, causing the glutamic acid (E) at amino acid position 89 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	0.31
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T;T;.;.;.;T;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;D;D;D;D;T;T;D;T;T
Polyphen		0.97	D;.;.;.;.;.;.;.;.;.
Vest4		0.81
MutPred		0.28		Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);.;Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);
MVP		0.69
MPC		0.36
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.69
gMVP		0.43

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: rs782193998; hg19: chr11-113195347;