chr22-43168917-G-T

Variant names:

• chr22-43168917-G-T
• rs117616050
• NM_015140.4:c.1645-5C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015140.4(TTLL12):​c.1645-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,607,664 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (94 hom.)
• Consequence: TTLL12 NM_015140.4 splice_region, intron
• Scores: Splicing: ADA: 0.05337
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0830
• Publications: 3 publications found

Genes affected

TTLL12 (HGNC:28974): (tubulin tyrosine ligase like 12) Enables H4K20me3 modified histone binding activity and tubulin binding activity. Involved in negative regulation of type I interferon-mediated signaling pathway and regulation of mitotic cell cycle. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 22-43168917-G-T is Benign according to our data. Variant chr22-43168917-G-T is described in ClinVar as Benign. ClinVar VariationId is 780201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00537 (818/152290) while in subpopulation EAS AF = 0.0443 (229/5172). AF 95% confidence interval is 0.0396. There are 12 homozygotes in GnomAd4. There are 516 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015140.4. 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
	TTLL12	NM_015140.4	MANE Select	c.1645-5C>A		splice_region intron	N/A	NP_055955.1	Q14166

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL12	ENST00000216129.7	TSL:1 MANE Select	c.1645-5C>A		splice_region intron	N/A	ENSP00000216129.6	Q14166
	TTLL12	ENST00000494035.1	TSL:2	c.-93-5C>A		splice_region intron	N/A	ENSP00000476297.1	V9GY16
	TTLL12	ENST00000484711.1	TSL:2	n.776-5C>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 819 AN: 152172 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0442

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00793 AC: 1908 AN: 240502 AF XY: 0.00745

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000613

Gnomad EAS exome AF: 0.0490

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00661

GnomAD4 exome AF: 0.00333 AC: 4840 AN: 1455374 Hom.: 94 Cov.: 30 AF XY: 0.00326 AC XY: 2356 AN XY: 723210

African (AFR) AF: 0.00114 AC: 38 AN: 33400

American (AMR) AF: 0.00106 AC: 47 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 15 AN: 26028

East Asian (EAS) AF: 0.0501 AC: 1980 AN: 39498

South Asian (SAS) AF: 0.00223 AC: 191 AN: 85594

European-Finnish (FIN) AF: 0.0341 AC: 1769 AN: 51870

Middle Eastern (MID) AF: 0.00127 AC: 7 AN: 5496

European-Non Finnish (NFE) AF: 0.000421 AC: 467 AN: 1108998

Other (OTH) AF: 0.00543 AC: 326 AN: 60064

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152290 Hom.: 12 Cov.: 33 AF XY: 0.00693 AC XY: 516 AN XY: 74438

African (AFR) AF: 0.00154 AC: 64 AN: 41566

American (AMR) AF: 0.00386 AC: 59 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0443 AC: 229 AN: 5172

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68022

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.083
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.053
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117616050; hg19: chr22-43564923;