15-43403697-G-T

Position:

• chr15-43403697-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_014444.5(TUBGCP4):​c.1746G>T​(p.Leu582=) 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:11 B:1
• Conservation: PhyloP100: 2.03

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-43403697-G-T is Pathogenic according to our data. Variant chr15-43403697-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43403697-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBGCP4	NM_014444.5	c.1746G>T	p.Leu582=	synonymous_variant	16/18	ENST00000564079.6	NP_055259.2
TP53BP1	NM_001141980.3	c.*3686C>A		3_prime_UTR_variant	28/28	ENST00000382044.9	NP_001135452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBGCP4	ENST00000564079.6	c.1746G>T	p.Leu582=	synonymous_variant	16/18	1	NM_014444.5	ENSP00000456648	A1
TP53BP1	ENST00000382044.9	c.*3686C>A		3_prime_UTR_variant	28/28	1	NM_001141980.3	ENSP00000371475	P4

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

GnomAD3 exomes AF: 0.000297 AC: 74 AN: 248998 Hom.: 0 AF XY: 0.000370 AC XY: 50 AN XY: 135084

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 SAS 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

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000899

Gnomad4 OTH exome AF: 0.000597

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

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000434

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly and chorioretinopathy 3 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2018	DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an amino acid substitution. This silent sequence change was previously reported in in the compound heterozygous state in a patient with TUBGCP4-related microcephaly and chorioretinopathy (PMID: 25817018). Functional analysis of individual fibroblasts demonstrated that the c.1746G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product (PMID: 25817018). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 04, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Universidade de São Paulo	Jun 27, 2022	This variant meets our criteria to be classified as pathogenic based upon segregation studies, low frequency in control samples, and in-silico evaluation of pathogenicity. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly and chorioretinopathy, 3, (MIM#616335). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of cDNA derived from an affected individual's fibroblasts has demonstrated this variant causes inframe exon 16 skipping, but also the retention of wildtype protein. The proportion of wildtype and mutant protein is unclear (PMID: 25817018). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (86 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Gamma tubulin complex component C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and is a recurring variant observed in compound heterozygous individuals with microcephaly, chorioretinopathy and intellectual disability (ClinVar, PMID: 25817018), and a homozygous individual with autism and ectasia of the optic nerve sheaths with no microcephaly or chorioretinopathy (PMID: 35418825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2024	Reported in the homozygous state in a proband with an atypical phenotype of autism spectrum disorder and ectasia of the optic nerve sheaths with a normal head circumference and no retinal anomalies (PMID: 35418825); Functional studies using fibroblasts from a patient suggest that the c.1746 G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product, abnormal microtubule organization, and altered cell morphology (PMID: 25817018); This variant is associated with the following publications: (PMID: 25817018, 31847883, 32270730, 33137195, 31964843, 35418825) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change affects codon 583 of the TUBGCP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TUBGCP4 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200092283, gnomAD 0.05%). This variant has been observed in individual(s) with microcephaly and chorioretinal dysplasia (PMID: 25817018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190123). Studies have shown that this variant results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 25817018). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive chorioretinopathy-microcephaly syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2018

The p.Leu582Leu variant in TUBGCP4 has been reported in the compound heterozygou s state (with loss of function variants) in 3 individuals with microcephaly with chorioretinopathy and segregated with disease in 1 affected relative (Scheideck er 2015). It has also been identified in 0.05% (66/128464) of European chromosom es by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 190123). In vitro functional studies support a splicing impact af fecting protein function (Scheidecker 2015). In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive microc ephaly with chorioretinopathy. ACMG/AMP Criteria applied: PM3_Strong, PP1, PS3_S upporting. -

TUBGCP4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.0
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs200092283; hg19: chr15-43695895;