22-43168801-T-G

Variant names:

• chr22-43168801-T-G
• rs201537260
• NM_015140.4:c.1756A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015140.4(TTLL12):​c.1756A>C​(p.Met586Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,419,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M586V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TTLL12 NM_015140.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.14
• Publications: 0 publications found

Genes affected

TTLL12 (HGNC:28974): (tubulin tyrosine ligase like 12) Enables H4K20me3 modified histone binding activity and tubulin binding activity. Involved in negative regulation of type I interferon-mediated signaling pathway and regulation of mitotic cell cycle. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015140.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL12	NM_015140.4	MANE Select	c.1756A>C	p.Met586Leu	missense	Exon 13 of 14	NP_055955.1	Q14166

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL12	ENST00000216129.7	TSL:1 MANE Select	c.1756A>C	p.Met586Leu	missense	Exon 13 of 14	ENSP00000216129.6	Q14166
	TTLL12	ENST00000494035.1	TSL:2	c.19A>C	p.Met7Leu	missense	Exon 3 of 4	ENSP00000476297.1	V9GY16
	TTLL12	ENST00000484711.1	TSL:2	n.887A>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419626 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702386

African (AFR) AF: 0.00 AC: 0 AN: 32452

American (AMR) AF: 0.00 AC: 0 AN: 37706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37170

South Asian (SAS) AF: 0.00 AC: 0 AN: 80960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091304

Other (OTH) AF: 0.00 AC: 0 AN: 58870

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.25
Sift	Uncertain	0.021	D
Sift4G	Benign	0.095	T
Polyphen		0.84	P
Vest4		0.73
MutPred		0.64		Loss of methylation at K588 (P = 0.0878)
MVP		0.19
MPC		0.33
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.79
Mutation Taster		=36/64	disease causing

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: rs201537260; hg19: chr22-43564807;