rs5759125

chr22-43059426-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.849C>T(p.Asp283=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,694 control chromosomes in the GnomAD database, including 31,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (6365 hom., cov: 33)
  • Exomes 𝑓: 0.14 (25228 hom.)
• Consequence: TTLL1 NM_012263.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.78

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=-0.4).
• BP6: Variant 22-43059426-G-A is Benign according to our data. Variant chr22-43059426-G-A is described in ClinVar as [Benign]. Clinvar id is 403578.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTLL1	NM_012263.5	c.849C>T	p.Asp283=	synonymous_variant	8/11	ENST00000266254.12
TTLL1	NR_027779.2	n.1157C>T		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL1	ENST00000266254.12	c.849C>T	p.Asp283=	synonymous_variant	8/11	1	NM_012263.5	P1
TTLL1	ENST00000331018.8	c.849C>T	p.Asp283=	synonymous_variant	6/8	1
TTLL1	ENST00000439248.5	c.*773C>T		3_prime_UTR_variant, NMD_transcript_variant	9/12	1
TTLL1	ENST00000440761.1	c.*741C>T		3_prime_UTR_variant, NMD_transcript_variant	9/12	5

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35143 AN: 151968 Hom.: 6351 Cov.: 33

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.218 AC: 54743 AN: 250880 Hom.: 10306 AF XY: 0.206 AC XY: 27874 AN XY: 135632

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.721

Gnomad SAS exome AF: 0.253

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.143 AC: 209381 AN: 1461608 Hom.: 25228 Cov.: 32 AF XY: 0.144 AC XY: 104794 AN XY: 727100

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.231 AC: 35198 AN: 152086 Hom.: 6365 Cov.: 33 AF XY: 0.234 AC XY: 17378 AN XY: 74336

Gnomad4 AFR AF: 0.429

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.693

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.215

Alfa AF: 0.136 Hom.: 2509

Bravo AF: 0.258

Asia WGS AF: 0.462 AC: 1605 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.107

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	-0.40
Cadd	Benign	12
Dann	Benign	0.70

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: rs5759125; hg19: chr22-43455432; COSMIC: COSV56738784;