chr22-43063840-G-A

Variant names:

• chr22-43063840-G-A
• rs1052160
• NM_012263.5:c.720C>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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.45
• Publications: 18 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=0.023).
• BP6: Variant 22-43063840-G-A is Benign according to our data. Variant chr22-43063840-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL1	NM_012263.5	MANE Select	c.720C>T	p.Leu240Leu	synonymous	Exon 7 of 11	NP_036395.1
	TTLL1	NR_027779.2		n.1028C>T		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL1	ENST00000266254.12	TSL:1 MANE Select	c.720C>T	p.Leu240Leu	synonymous	Exon 7 of 11	ENSP00000266254.7
	TTLL1	ENST00000331018.8	TSL:1	c.720C>T	p.Leu240Leu	synonymous	Exon 5 of 8	ENSP00000333734.7
	TTLL1	ENST00000439248.5	TSL:1	n.*644C>T		non_coding_transcript_exon	Exon 8 of 12	ENSP00000401518.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34005 AN: 152048 Hom.: 4471 Cov.: 32

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

GnomAD2 exomes AF: 0.251 AC: 63192 AN: 251320 AF XY: 0.257

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 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.: 35 AF XY: 0.274 AC XY: 198940 AN XY: 727020

African (AFR) AF: 0.104 AC: 3496 AN: 33468

American (AMR) AF: 0.256 AC: 11440 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11559 AN: 26128

East Asian (EAS) AF: 0.000957 AC: 38 AN: 39696

South Asian (SAS) AF: 0.265 AC: 22868 AN: 86248

European-Finnish (FIN) AF: 0.267 AC: 14247 AN: 53410

Middle Eastern (MID) AF: 0.375 AC: 2165 AN: 5768

European-Non Finnish (NFE) AF: 0.284 AC: 315735 AN: 1111626

Other (OTH) AF: 0.274 AC: 16550 AN: 60374

GnomAD4 genome AF: 0.224 AC: 34015 AN: 152166 Hom.: 4473 Cov.: 32 AF XY: 0.221 AC XY: 16468 AN XY: 74390

African (AFR) AF: 0.107 AC: 4455 AN: 41542

American (AMR) AF: 0.250 AC: 3810 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1506 AN: 3470

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5182

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2617 AN: 10592

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19375 AN: 67970

Other (OTH) AF: 0.257 AC: 541 AN: 2108

Alfa AF: 0.273 Hom.: 9858

Bravo AF: 0.220

Asia WGS AF: 0.117 AC: 411 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.298

ClinVar

ClinVar submissions as Germline

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	-0.37
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		1.4
Mutation Taster		=97/3	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: rs1052160; hg19: chr22-43459846; COSMIC: COSV56741011;