chr22-43051885-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_012263.5(TTLL1):c.894G>A(p.Pro298Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,613,604 control chromosomes in the GnomAD database, including 1,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 127 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1771 hom. )

Consequence

TTLL1
NM_012263.5 splice_region, synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.61

Publications

7 publications found

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:

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

TTLL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 22-43051885-C-T is Benign according to our data. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-43051885-C-T is described in CliVar as Benign. Clinvar id is 403577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL1	NM_012263.5 link	c.894G>A	p.Pro298Pro	splice_region_variant, synonymous_variant	Exon 9 of 11	ENST00000266254.12	NP_036395.1	O95922-1A0A024R4U6
TTLL1	NR_027779.2 link	n.1202G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 12
TTLL1-AS1	NR_125362.1 link	n.1772-170C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12 link	c.894G>A	p.Pro298Pro	splice_region_variant, synonymous_variant	Exon 9 of 11	1	NM_012263.5	ENSP00000266254.7		O95922-1

Frequencies

GnomAD3 genomes

AF:

0.0331

AC:

5029

AN:

151978

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00978

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0564

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0274

GnomAD2 exomes

AF:

0.0335

AC:

8416

AN:

251380

AF XY:

0.0341

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0516

Gnomad NFE exome

AF:

0.0503

Gnomad OTH exome

AF:

0.0360

GnomAD4 exome

AF:

0.0460

AC:

67294

AN:

1461508

Hom.:

1771

Cov.:

AF XY:

0.0449

AC XY:

32651

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00842

AC:

282

AN:

33480

American (AMR)

AF:

0.0181

AC:

809

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0261

AC:

681

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0114

AC:

983

AN:

86256

European-Finnish (FIN)

AF:

0.0539

AC:

2878

AN:

53376

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0532

AC:

59137

AN:

1111690

Other (OTH)

AF:

0.0404

AC:

2441

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

3050

6100

9150

12200

15250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2174

4348

6522

8696

10870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0331

AC:

5028

AN:

152096

Hom.:

127

Cov.:

AF XY:

0.0327

AC XY:

2430

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00973

AC:

404

AN:

41526

American (AMR)

AF:

0.0274

AC:

418

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00850

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0564

AC:

597

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3386

AN:

67972

Other (OTH)

AF:

0.0271

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

245

490

735

980

1225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0390

Hom.:

161

Bravo

AF:

0.0297

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0457

EpiControl

AF:

0.0462

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, silent -

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

-0.44

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

-1.6

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.87

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over