22-43051885-C-T

Variant names:

• chr22-43051885-C-T
• rs9607998
• NM_012263.5:c.894G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 7 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]

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

ACMG classification

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 ClinVar as Benign. ClinVar VariationId 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.

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.894G>A	p.Pro298Pro	splice_region synonymous	Exon 9 of 11	NP_036395.1
	TTLL1	NR_027779.2		n.1202G>A		splice_region non_coding_transcript_exon	Exon 10 of 12
	TTLL1-AS1	NR_125362.1		n.1772-170C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL1	ENST00000266254.12	TSL:1 MANE Select	c.894G>A	p.Pro298Pro	splice_region synonymous	Exon 9 of 11	ENSP00000266254.7
	TTLL1	ENST00000439248.5	TSL:1	n.*818G>A		splice_region non_coding_transcript_exon	Exon 10 of 12	ENSP00000401518.1
	TTLL1	ENST00000439248.5	TSL:1	n.*818G>A		3_prime_UTR	Exon 10 of 12	ENSP00000401518.1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5029 AN: 151978 Hom.: 127 Cov.: 32

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

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.: 31 AF XY: 0.0449 AC XY: 32651 AN XY: 727060

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: 0 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: 83 AN: 5768

European-Non Finnish (NFE) AF: 0.0532 AC: 59137 AN: 1111690

Other (OTH) AF: 0.0404 AC: 2441 AN: 60386

GnomAD4 genome AF: 0.0331 AC: 5028 AN: 152096 Hom.: 127 Cov.: 32 AF XY: 0.0327 AC XY: 2430 AN XY: 74362

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: 0 AN: 5166

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4824

European-Finnish (FIN) AF: 0.0564 AC: 597 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3386 AN: 67972

Other (OTH) AF: 0.0271 AC: 57 AN: 2106

Alfa AF: 0.0390 Hom.: 161

Bravo AF: 0.0297

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.0457

EpiControl AF: 0.0462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		-1.6
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9607998; hg19: chr22-43447891;