22-43059451-T-C

Position:

• chr22-43059451-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012263.5(TTLL1):​c.824A>G​(p.Lys275Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,080 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: TTLL1 NM_012263.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.272

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037164092).
• BP6: Variant 22-43059451-T-C is Benign according to our data. Variant chr22-43059451-T-C is described in ClinVar as [Benign]. Clinvar id is 720636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00703 (1071/152272) while in subpopulation AFR AF= 0.0245 (1017/41568). AF 95% confidence interval is 0.0232. There are 10 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL1	NM_012263.5	c.824A>G	p.Lys275Arg	missense_variant	8/11	ENST00000266254.12	NP_036395.1
TTLL1	NR_027779.2	n.1132A>G		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12	c.824A>G	p.Lys275Arg	missense_variant	8/11	1	NM_012263.5	ENSP00000266254	P1
TTLL1	ENST00000331018.8	c.824A>G	p.Lys275Arg	missense_variant	6/8	1		ENSP00000333734
TTLL1	ENST00000439248.5	c.*748A>G		3_prime_UTR_variant, NMD_transcript_variant	9/12	1		ENSP00000401518
TTLL1	ENST00000440761.1	c.*716A>G		3_prime_UTR_variant, NMD_transcript_variant	9/12	5		ENSP00000403332

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152154 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00187 AC: 469 AN: 251058 Hom.: 6 AF XY: 0.00139 AC XY: 188 AN XY: 135720

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000729 AC: 1066 AN: 1461808 Hom.: 12 Cov.: 31 AF XY: 0.000630 AC XY: 458 AN XY: 727202

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00703 AC: 1071 AN: 152272 Hom.: 10 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74458

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00132 Hom.: 3

Bravo AF: 0.00799

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00216 AC: 262

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.045
Sift	Benign	0.38	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0010	B;B
Vest4		0.10
MVP		0.099
MPC		0.36
ClinPred		0.0040	T
GERP RS		-1.3
Varity_R		0.032
gMVP		0.42

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: rs35714805; hg19: chr22-43455457;