NM_017868.4:c.139C>A

Variant names:

• chr11-113323368-C-A
• rs1947468829
• NM_017868.4:c.139C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017868.4(TTC12):​c.139C>A​(p.Leu47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L47F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• Publications: 0 publications found

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]

TTC12 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 45

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052556872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4	c.139C>A	p.Leu47Ile	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.139C>A	p.Leu47Ile	missense_variant	Exon 3 of 22	2	NM_017868.4	ENSP00000433757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.1
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T;T;T;.;.;.;T;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.85	T;D;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.;.;M;.
PhyloP100		-0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.030	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T;T
Polyphen		0.10	B;.;.;.;.;.;.;.;.;.
Vest4		0.15
MutPred		0.23		Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);.;Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);Gain of methylation at K43 (P = 0.0558);
MVP		0.18
MPC		0.085
ClinPred		0.15	T
GERP RS		-0.58
Varity_R		0.087
gMVP		0.074
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1947468829; hg19: chr11-113194090;