rs1132079

Positions:

• chr22-43059525-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000266254.12(TTLL1):​c.750G>A​(p.Glu250=) 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 ENST00000266254.12 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
TTLL1	NM_012263.5	c.750G>A	p.Glu250=	splice_region_variant, synonymous_variant	8/11	ENST00000266254.12	NP_036395.1
TTLL1	NR_027779.2	n.1058G>A		splice_region_variant, non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12	c.750G>A	p.Glu250=	splice_region_variant, synonymous_variant	8/11	1	NM_012263.5	ENSP00000266254	P1
TTLL1	ENST00000331018.8	c.750G>A	p.Glu250=	splice_region_variant, synonymous_variant	6/8	1		ENSP00000333734
TTLL1	ENST00000439248.5	c.*674G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	9/12	1		ENSP00000401518
TTLL1	ENST00000440761.1	c.*642G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	9/12	5		ENSP00000403332

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

GnomAD3 exomes AF: 0.251 AC: 61642 AN: 246058 Hom.: 8810 AF XY: 0.257 AC XY: 34119 AN XY: 132996

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 SAS exome AF: 0.255

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

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.438

Gnomad4 EAS exome AF: 0.000959

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.274

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

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.259

Alfa AF: 0.278 Hom.: 8955

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.1
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

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