rs34273213

Positions:

• chr22-50229576-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_020461.4(TUBGCP6):​c.1118C>T​(p.Pro373Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,585,532 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P373P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: TUBGCP6 NM_020461.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001693
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.198

Genes affected

TUBGCP6 (HGNC:18127): (tubulin gamma complex component 6) The protein encoded by this gene is part of a large multisubunit complex required for microtubule nucleation at the centrosome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046064854).
• BP6: Variant 22-50229576-G-A is Benign according to our data. Variant chr22-50229576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00315 (480/152268) while in subpopulation AFR AF= 0.0109 (453/41548). AF 95% confidence interval is 0.0101. There are 4 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBGCP6	NM_020461.4	c.1118C>T	p.Pro373Leu	missense_variant, splice_region_variant	4/25	ENST00000248846.10
TUBGCP6	XR_001755343.3	n.1682C>T		splice_region_variant, non_coding_transcript_exon_variant	4/20
TUBGCP6	XR_007067982.1	n.1682C>T		splice_region_variant, non_coding_transcript_exon_variant	4/19
TUBGCP6	XR_938347.3	n.1682C>T		splice_region_variant, non_coding_transcript_exon_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBGCP6	ENST00000248846.10	c.1118C>T	p.Pro373Leu	missense_variant, splice_region_variant	4/25	1	NM_020461.4	P1
TUBGCP6	ENST00000439308.6	c.1118C>T	p.Pro373Leu	missense_variant, splice_region_variant	4/25	1
TUBGCP6	ENST00000498611.5	n.1651C>T		splice_region_variant, non_coding_transcript_exon_variant	4/23	1
TUBGCP6	ENST00000434349.1	c.350C>T	p.Pro117Leu	missense_variant, splice_region_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152150 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000832 AC: 166 AN: 199514 Hom.: 1 AF XY: 0.000584 AC XY: 63 AN XY: 107890

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000700

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.000373 AC: 535 AN: 1433264 Hom.: 4 Cov.: 31 AF XY: 0.000318 AC XY: 226 AN XY: 710682

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000733

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.0000527

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000400

Gnomad4 OTH exome AF: 0.000574

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00324 AC XY: 241 AN XY: 74450

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000739 Hom.: 0

Bravo AF: 0.00342

ESP6500AA AF: 0.00957 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000830 AC: 100

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 24, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.3
DANN	Benign	0.79
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.052
Sift	Benign	0.38	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.017	B;.
Vest4		0.13
MVP		0.41
MPC		0.19
ClinPred		0.0023	T
GERP RS		0.47
Varity_R		0.028
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs34273213; hg19: chr22-50668005;