chr15-43403697-G-T

Variant names:

• chr15-43403697-G-T
• rs200092283
• NM_014444.5:c.1746G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_014444.5(TUBGCP4):​c.1746G>T​(p.Leu582Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,612,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: TUBGCP4 NM_014444.5 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.03
• Publications: 10 publications found

Genes affected

TUBGCP4 (HGNC:16691): (tubulin gamma complex component 4) This gene encodes a component of the gamma-tubulin ring complex, which is required for microtubule nucleation. In mammalian cells, the protein localizes to centrosomes in association with gamma-tubulin. Crystal structure analysis revealed a structure composed of five helical bundles arranged around conserved hydrophobic cores. An exposed surface area located in the C-terminal domain is essential and sufficient for direct binding to gamma-tubulin. Mutations in this gene that alter microtubule organization are associated with microcephaly and chorioretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

TP53BP1 (HGNC:11999): (tumor protein p53 binding protein 1) This gene encodes a protein that functions in the DNA double-strand break repair pathway choice, promoting non-homologous end joining (NHEJ) pathways, and limiting homologous recombination. This protein plays multiple roles in the DNA damage response, including promoting checkpoint signaling following DNA damage, acting as a scaffold for recruitment of DNA damage response proteins to damaged chromatin, and promoting NHEJ pathways by limiting end resection following a double-strand break. These roles are also important during V(D)J recombination, class switch recombination and at unprotected telomeres. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 15-43403697-G-T is Pathogenic according to our data. Variant chr15-43403697-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 190123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014444.5. 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
	TUBGCP4	NM_014444.5	MANE Select	c.1746G>T	p.Leu582Leu	synonymous	Exon 16 of 18	NP_055259.2
	TP53BP1	NM_001141980.3	MANE Select	c.*3686C>A		3_prime_UTR	Exon 28 of 28	NP_001135452.1	Q12888-2
	TUBGCP4	NM_001286414.3		c.1749G>T	p.Leu583Leu	synonymous	Exon 16 of 18	NP_001273343.1	Q9UGJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP4	ENST00000564079.6	TSL:1 MANE Select	c.1746G>T	p.Leu582Leu	synonymous	Exon 16 of 18	ENSP00000456648.2	Q9UGJ1-2
	TUBGCP4	ENST00000260383.11	TSL:1	c.1749G>T	p.Leu583Leu	synonymous	Exon 16 of 18	ENSP00000260383.7	Q9UGJ1-1
	TP53BP1	ENST00000382044.9	TSL:1 MANE Select	c.*3686C>A		3_prime_UTR	Exon 28 of 28	ENSP00000371475.5	Q12888-2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000297 AC: 74 AN: 248998 AF XY: 0.000370

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000723 AC: 1056 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.000736 AC XY: 535 AN XY: 726430

African (AFR) AF: 0.0000598 AC: 2 AN: 33428

American (AMR) AF: 0.000380 AC: 17 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4794

European-Non Finnish (NFE) AF: 0.000899 AC: 999 AN: 1111698

Other (OTH) AF: 0.000597 AC: 36 AN: 60260

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74444

African (AFR) AF: 0.000144 AC: 6 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000434

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Microcephaly and chorioretinopathy 3 (6)
4	-	-	not provided (4)
1	-	-	Autosomal recessive chorioretinopathy-microcephaly syndrome (1)
1	-	-	TUBGCP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.0
DANN	Benign	0.80
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -14

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

Other links and lift over

dbSNP: rs200092283; hg19: chr15-43695895;