22-43039806-C-T

Variant names:

• chr22-43039806-C-T
• rs1052163
• NM_012263.5:c.1242G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012263.5(TTLL1):​c.1242G>A​(p.Ser414Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,284 control chromosomes in the GnomAD database, including 56,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9371 hom., cov: 31)
  • Exomes 𝑓: 0.22 (47063 hom.)
• Consequence: TTLL1 NM_012263.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78
• Publications: 17 publications found

Genes affected

TTLL1 (HGNC:1312): (TTL family tubulin polyglutamylase complex subunit L1) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to act upstream of or within several processes, including cerebellar Purkinje cell differentiation; mucociliary clearance; and regulation of blastocyst development. Predicted to be located in cytoplasm; extracellular region; and microtubule cytoskeleton. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL1-AS1 (HGNC:40111): (TTLL1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-43039806-C-T is Benign according to our data. Variant chr22-43039806-C-T is described in ClinVar as Benign. ClinVar VariationId is 403576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL1	NM_012263.5	c.1242G>A	p.Ser414Ser	synonymous_variant	Exon 11 of 11	ENST00000266254.12	NP_036395.1
TTLL1	NR_027779.2	n.1550G>A		non_coding_transcript_exon_variant	Exon 12 of 12
TTLL1-AS1	NR_125362.1	n.1222C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12	c.1242G>A	p.Ser414Ser	synonymous_variant	Exon 11 of 11	1	NM_012263.5	ENSP00000266254.7

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46440 AN: 151840 Hom.: 9373 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.300 AC: 75097 AN: 249952 AF XY: 0.288

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.842

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.217 AC: 316923 AN: 1461326 Hom.: 47063 Cov.: 32 AF XY: 0.218 AC XY: 158429 AN XY: 726920

African (AFR) AF: 0.490 AC: 16398 AN: 33456

American (AMR) AF: 0.452 AC: 20206 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4590 AN: 26112

East Asian (EAS) AF: 0.804 AC: 31885 AN: 39674

South Asian (SAS) AF: 0.337 AC: 29030 AN: 86224

European-Finnish (FIN) AF: 0.140 AC: 7483 AN: 53352

Middle Eastern (MID) AF: 0.177 AC: 1019 AN: 5768

European-Non Finnish (NFE) AF: 0.172 AC: 190816 AN: 1111670

Other (OTH) AF: 0.257 AC: 15496 AN: 60368

GnomAD4 genome AF: 0.306 AC: 46467 AN: 151958 Hom.: 9371 Cov.: 31 AF XY: 0.311 AC XY: 23079 AN XY: 74290

African (AFR) AF: 0.478 AC: 19829 AN: 41440

American (AMR) AF: 0.393 AC: 5990 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 588 AN: 3472

East Asian (EAS) AF: 0.817 AC: 4218 AN: 5160

South Asian (SAS) AF: 0.368 AC: 1771 AN: 4808

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10580

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11779 AN: 67948

Other (OTH) AF: 0.304 AC: 639 AN: 2102

Alfa AF: 0.242 Hom.: 3644

Bravo AF: 0.335

Asia WGS AF: 0.555 AC: 1929 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.177

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.47
DANN	Benign	0.83
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs1052163; hg19: chr22-43435812; COSMIC: COSV56737879;