Genetic Variant TTLL12:c.1645-5C>A (chr22-43168917-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Variant links:

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]

TTLL12 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL12	NM_015140.4 link	c.1645-5C>A		splice_region_variant, intron_variant	Intron 12 of 13	ENST00000216129.7	NP_055955.1	Q14166A0A024R4U3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTLL12	ENST00000216129.7 link	c.1645-5C>A	splice_region_variant, intron_variant	Intron 12 of 13	1	NM_015140.4	ENSP00000216129.6	Q14166
TTLL12	ENST00000494035.1 link	c.-93-5C>A	splice_region_variant, intron_variant	Intron 2 of 3	2		ENSP00000476297.1	V9GY16
TTLL12	ENST00000484711.1 link	n.776-5C>A	splice_region_variant, intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

819

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00793

AC:

1908

AN:

240502

Hom.:

AF XY:

0.00745

AC XY:

974

AN XY:

130778

show subpopulations

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 SAS exome

AF:

0.00225

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.:

Cov.:

AF XY:

0.00326

AC XY:

2356

AN XY:

723210

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00106

Gnomad4 ASJ exome

AF:

0.000576

Gnomad4 EAS exome

AF:

0.0501

Gnomad4 SAS exome

AF:

0.00223

Gnomad4 FIN exome

AF:

0.0341

Gnomad4 NFE exome

AF:

0.000421

Gnomad4 OTH exome

AF:

0.00543

GnomAD4 genome

AF:

0.00537

AC:

818

AN:

152290

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

516

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0443

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0361

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00326

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over