chr22-43059525-C-T

Variant names:

• chr22-43059525-C-T
• rs1132079
• NM_012263.5:c.750G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_012263.5(TTLL1):​c.750G>A​(p.Glu250Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,611,020 control chromosomes in the GnomAD database, including 61,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4466 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57237 hom.)
• Consequence: TTLL1 NM_012263.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880
• Publications: 14 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-43059525-C-T is Benign according to our data. Variant chr22-43059525-C-T is described in ClinVar as Benign. ClinVar VariationId is 403579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL1	NM_012263.5	c.750G>A	p.Glu250Glu	splice_region_variant, synonymous_variant	Exon 8 of 11	ENST00000266254.12	NP_036395.1
TTLL1	NR_027779.2	n.1058G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12	c.750G>A	p.Glu250Glu	splice_region_variant, synonymous_variant	Exon 8 of 11	1	NM_012263.5	ENSP00000266254.7

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33962 AN: 151946 Hom.: 4464 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.251 AC: 61642 AN: 246058 AF XY: 0.257

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.00115

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.272 AC: 397544 AN: 1458954 Hom.: 57237 Cov.: 35 AF XY: 0.274 AC XY: 198635 AN XY: 725610

African (AFR) AF: 0.104 AC: 3488 AN: 33416

American (AMR) AF: 0.255 AC: 11263 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 11379 AN: 25972

East Asian (EAS) AF: 0.000959 AC: 38 AN: 39618

South Asian (SAS) AF: 0.265 AC: 22802 AN: 85980

European-Finnish (FIN) AF: 0.266 AC: 14194 AN: 53286

Middle Eastern (MID) AF: 0.378 AC: 2177 AN: 5760

European-Non Finnish (NFE) AF: 0.284 AC: 315705 AN: 1110500

Other (OTH) AF: 0.274 AC: 16498 AN: 60270

GnomAD4 genome AF: 0.223 AC: 33971 AN: 152066 Hom.: 4466 Cov.: 32 AF XY: 0.221 AC XY: 16448 AN XY: 74342

African (AFR) AF: 0.107 AC: 4438 AN: 41502

American (AMR) AF: 0.250 AC: 3805 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1488 AN: 3468

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5182

South Asian (SAS) AF: 0.251 AC: 1207 AN: 4814

European-Finnish (FIN) AF: 0.246 AC: 2603 AN: 10568

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19382 AN: 67970

Other (OTH) AF: 0.259 AC: 546 AN: 2112

Alfa AF: 0.264 Hom.: 12969

Bravo AF: 0.220

Asia WGS AF: 0.118 AC: 412 AN: 3478

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	-0.45
CADD	Benign	7.1
DANN	Benign	0.64
PhyloP100		0.088
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1132079; hg19: chr22-43455531; COSMIC: COSV56739655;