rs5759125

Variant names:

• chr22-43059426-G-A
• rs5759125
• NM_012263.5:c.849C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012263.5(TTLL1):​c.849C>T​(p.Asp283Asp) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.171).
• BP6: Variant 22-43059426-G-A is Benign according to our data. Variant chr22-43059426-G-A is described in ClinVar as Benign. ClinVar VariationId is 403578.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 = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012263.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL1	NM_012263.5	MANE Select	c.849C>T	p.Asp283Asp	synonymous	Exon 8 of 11	NP_036395.1	O95922-1
	TTLL1	NR_027779.2		n.1157C>T		non_coding_transcript_exon	Exon 9 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL1	ENST00000266254.12	TSL:1 MANE Select	c.849C>T	p.Asp283Asp	synonymous	Exon 8 of 11	ENSP00000266254.7	O95922-1
	TTLL1	ENST00000331018.8	TSL:1	c.849C>T	p.Asp283Asp	synonymous	Exon 6 of 8	ENSP00000333734.7	O95922-4
	TTLL1	ENST00000439248.5	TSL:1	n.*773C>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000401518.1	O95922-2

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

GnomAD2 exomes AF: 0.218 AC: 54743 AN: 250880 AF XY: 0.206

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 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

African (AFR) AF: 0.432 AC: 14443 AN: 33446

American (AMR) AF: 0.328 AC: 14643 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3139 AN: 26126

East Asian (EAS) AF: 0.665 AC: 26396 AN: 39676

South Asian (SAS) AF: 0.245 AC: 21140 AN: 86238

European-Finnish (FIN) AF: 0.0566 AC: 3023 AN: 53410

Middle Eastern (MID) AF: 0.116 AC: 671 AN: 5760

European-Non Finnish (NFE) AF: 0.104 AC: 115287 AN: 1111888

Other (OTH) AF: 0.176 AC: 10639 AN: 60380

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

African (AFR) AF: 0.429 AC: 17794 AN: 41468

American (AMR) AF: 0.259 AC: 3963 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 397 AN: 3470

East Asian (EAS) AF: 0.693 AC: 3570 AN: 5154

South Asian (SAS) AF: 0.266 AC: 1284 AN: 4820

European-Finnish (FIN) AF: 0.0564 AC: 597 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7023 AN: 67998

Other (OTH) AF: 0.215 AC: 454 AN: 2110

Alfa AF: 0.155 Hom.: 4877

Bravo AF: 0.258

Asia WGS AF: 0.462 AC: 1605 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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