Genetic Variant NM_012263.5:c.1242G>A (chr22-43039806-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_012263.5(TTLL1):c.1242G>A(p.Ser414Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,284 control chromosomes in the GnomAD database, including 56,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 9371 hom., cov: 31)

Exomes 𝑓: 0.22 ( 47063 hom. )

Consequence

TTLL1
NM_012263.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.78

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 22-43039806-C-T is Benign according to our data. Variant chr22-43039806-C-T is described in ClinVar as [Benign]. Clinvar id is 403576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.78 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL1	NM_012263.5 link	c.1242G>A	p.Ser414Ser	synonymous_variant	Exon 11 of 11	ENST00000266254.12	NP_036395.1	O95922-1A0A024R4U6
TTLL1	NR_027779.2 link	n.1550G>A		non_coding_transcript_exon_variant	Exon 12 of 12
TTLL1-AS1	NR_125362.1 link	n.1222C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12 link	c.1242G>A	p.Ser414Ser	synonymous_variant	Exon 11 of 11	1	NM_012263.5	ENSP00000266254.7		O95922-1

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46440

AN:

151840

Hom.:

9373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.818

Gnomad SAS

AF:

0.371

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.305

GnomAD3 exomes

AF:

0.300

AC:

75097

AN:

249952

Hom.:

16350

AF XY:

0.288

AC XY:

38979

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.487

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.842

Gnomad SAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.171

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

AF:

0.217

AC:

316923

AN:

1461326

Hom.:

47063

Cov.:

AF XY:

0.218

AC XY:

158429

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.490

Gnomad4 AMR exome

AF:

0.452

Gnomad4 ASJ exome

AF:

0.176

Gnomad4 EAS exome

AF:

0.804

Gnomad4 SAS exome

AF:

0.337

Gnomad4 FIN exome

AF:

0.140

Gnomad4 NFE exome

AF:

0.172

Gnomad4 OTH exome

AF:

0.257

GnomAD4 genome

AF:

0.306

AC:

46467

AN:

151958

Hom.:

9371

Cov.:

AF XY:

0.311

AC XY:

23079

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.478

Gnomad4 AMR

AF:

0.393

Gnomad4 ASJ

AF:

0.169

Gnomad4 EAS

AF:

0.817

Gnomad4 SAS

AF:

0.368

Gnomad4 FIN

AF:

0.143

Gnomad4 NFE

AF:

0.173

Gnomad4 OTH

AF:

0.304

Alfa

AF:

0.221

Hom.:

1994

Bravo

AF:

0.335

Asia WGS

AF:

0.555

AC:

1929

AN:

3478

EpiCase

AF:

0.172

EpiControl

AF:

0.177

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

-0.70

CADD

Benign

0.47

DANN

Benign

0.83

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