22-43183043-T-C

Position:

• chr22-43183043-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015140.4(TTLL12):​c.284A>G​(p.Asn95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 1,613,948 control chromosomes in the GnomAD database, including 8,588 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.088 (661 hom., cov: 33)
  • Exomes 𝑓: 0.099 (7927 hom.)
• Consequence: TTLL12 NM_015140.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014352798).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL12	NM_015140.4	c.284A>G	p.Asn95Ser	missense_variant	2/14	ENST00000216129.7	NP_055955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL12	ENST00000216129.7	c.284A>G	p.Asn95Ser	missense_variant	2/14	1	NM_015140.4	ENSP00000216129	P1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13365 AN: 152126 Hom.: 661 Cov.: 33

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0802 AC: 20156 AN: 251168 Hom.: 960 AF XY: 0.0806 AC XY: 10944 AN XY: 135824

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.0838

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0533

Gnomad FIN exome AF: 0.0882

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.0988 AC: 144349 AN: 1461704 Hom.: 7927 Cov.: 32 AF XY: 0.0977 AC XY: 71071 AN XY: 727158

Gnomad4 AFR exome AF: 0.0728

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.0816

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0540

Gnomad4 FIN exome AF: 0.0840

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0932

GnomAD4 genome AF: 0.0879 AC: 13377 AN: 152244 Hom.: 661 Cov.: 33 AF XY: 0.0853 AC XY: 6348 AN XY: 74438

Gnomad4 AFR AF: 0.0732

Gnomad4 AMR AF: 0.0792

Gnomad4 ASJ AF: 0.0819

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.0814

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0993

Alfa AF: 0.102 Hom.: 2095

Bravo AF: 0.0883

TwinsUK AF: 0.110 AC: 407

ALSPAC AF: 0.120 AC: 462

ESP6500AA AF: 0.0726 AC: 320

ESP6500EA AF: 0.108 AC: 930

ExAC AF: 0.0797 AC: 9673

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.20
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.044	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.23	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.043
Sift	Benign	0.88	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.072
ClinPred		0.00029	T
GERP RS		0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.19

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: rs13058467; hg19: chr22-43579049; COSMIC: COSV53354417;