rs1052160

chr22-43063840-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_012263.5(TTLL1):c.720C>T(p.Leu240=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,586 control chromosomes in the GnomAD database, including 61,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4473 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57412 hom.)
• Consequence: TTLL1 NM_012263.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 22-43063840-G-A is Benign according to our data. Variant chr22-43063840-G-A is described in ClinVar as [Benign]. Clinvar id is 403580.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• 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	UniProt
TTLL1	NM_012263.5	c.720C>T	p.Leu240=	synonymous_variant	7/11	ENST00000266254.12
TTLL1	NR_027779.2	n.1028C>T		non_coding_transcript_exon_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL1	ENST00000266254.12	c.720C>T	p.Leu240=	synonymous_variant	7/11	1	NM_012263.5	P1
TTLL1	ENST00000331018.8	c.720C>T	p.Leu240=	synonymous_variant	5/8	1
TTLL1	ENST00000439248.5	c.*644C>T		3_prime_UTR_variant, NMD_transcript_variant	8/12	1
TTLL1	ENST00000440761.1	c.*612C>T		3_prime_UTR_variant, NMD_transcript_variant	8/12	5

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34005 AN: 152048 Hom.: 4471 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.251 AC: 63192 AN: 251320 Hom.: 9170 AF XY: 0.257 AC XY: 34970 AN XY: 135834

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.272 AC: 398098 AN: 1461420 Hom.: 57412 Cov.: 35 AF XY: 0.274 AC XY: 198940 AN XY: 727020

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.442

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.224 AC: 34015 AN: 152166 Hom.: 4473 Cov.: 32 AF XY: 0.221 AC XY: 16468 AN XY: 74390

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.257

Alfa AF: 0.279 Hom.: 8194

Bravo AF: 0.220

Asia WGS AF: 0.117 AC: 411 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	7.6
Dann	Benign	0.75

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: rs1052160; hg19: chr22-43459846; COSMIC: COSV56741011;