rs117773969

Positions:

• chr15-43395164-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014444.5(TUBGCP4):​c.1065+7G>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 0.00551 in 1,613,760 control chromosomes in the GnomAD database, including 47 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (46 hom.)
• Consequence: TUBGCP4 NM_014444.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001454
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-43395164-G-A is Benign according to our data. Variant chr15-43395164-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 437137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43395164-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00377 (574/152188) while in subpopulation NFE AF= 0.00634 (431/67990). AF 95% confidence interval is 0.00584. There are 1 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP4	NM_014444.5	c.1065+7G>A		splice_region_variant, intron_variant		ENST00000564079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP4	ENST00000564079.6	c.1065+7G>A		splice_region_variant, intron_variant		1	NM_014444.5	A1
TUBGCP4	ENST00000260383.11	c.1065+7G>A		splice_region_variant, intron_variant		1		P4
TUBGCP4	ENST00000561691.5	c.821+7G>A		splice_region_variant, intron_variant, NMD_transcript_variant		1
TUBGCP4	ENST00000563963.1	n.1084G>A		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00634

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00388 AC: 968 AN: 249520 Hom.: 4 AF XY: 0.00386 AC XY: 523 AN XY: 135370

Gnomad AFR exome AF: 0.000968

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00237

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00569 AC: 8311 AN: 1461572 Hom.: 46 Cov.: 30 AF XY: 0.00555 AC XY: 4033 AN XY: 727104

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.00692

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74420

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00634

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00511 Hom.: 0

Bravo AF: 0.00429

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TUBGCP4: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs117773969; hg19: chr15-43687362; COSMIC: COSV105871535; COSMIC: COSV105871535;