Genetic Variant NM_012263.5:c.720C>T (chr22-43063840-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_012263.5(TTLL1):c.720C>T(p.Leu240Leu) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.45

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
TTLL1	NM_012263.5 link	c.720C>T	p.Leu240Leu	synonymous_variant	Exon 7 of 11	ENST00000266254.12	NP_036395.1	O95922-1A0A024R4U6
TTLL1	NR_027779.2 link	n.1028C>T		non_coding_transcript_exon_variant	Exon 8 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12 link	c.720C>T	p.Leu240Leu	synonymous_variant	Exon 7 of 11	1	NM_012263.5	ENSP00000266254.7		O95922-1

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34005

AN:

152048

Hom.:

4471

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.274

AC XY:

198940

AN XY:

727020

show subpopulations

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.:

AF XY:

0.221

AC XY:

16468

AN XY:

74390

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over