rs4838865

Variant names:

• chr22-50226183-A-G
• rs4838865
• NM_020461.4:c.1700T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020461.4(TUBGCP6):​c.1700T>C​(p.Leu567Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,613,956 control chromosomes in the GnomAD database, including 482,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L567L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (51135 hom., cov: 32)
  • Exomes 𝑓: 0.77 (431130 hom.)
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.798
• Publications: 54 publications found

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]

TUBGCP6 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.319099E-7).
• BP6: Variant 22-50226183-A-G is Benign according to our data. Variant chr22-50226183-A-G is described in ClinVar as Benign. ClinVar VariationId is 518329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020461.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	NM_020461.4	MANE Select	c.1700T>C	p.Leu567Ser	missense	Exon 9 of 25	NP_065194.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.1700T>C	p.Leu567Ser	missense	Exon 9 of 25	ENSP00000248846.5
	TUBGCP6	ENST00000439308.7	TSL:1	n.1700T>C		non_coding_transcript_exon	Exon 9 of 25	ENSP00000397387.2
	TUBGCP6	ENST00000498611.5	TSL:1	n.2233T>C		non_coding_transcript_exon	Exon 9 of 23

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123790 AN: 152028 Hom.: 51086 Cov.: 32

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.894

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.791

GnomAD2 exomes AF: 0.782 AC: 196476 AN: 251388 AF XY: 0.788

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.830

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.770

GnomAD4 exome AF: 0.766 AC: 1120144 AN: 1461810 Hom.: 431130 Cov.: 76 AF XY: 0.769 AC XY: 559426 AN XY: 727198

African (AFR) AF: 0.959 AC: 32124 AN: 33480

American (AMR) AF: 0.662 AC: 29629 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 18704 AN: 26136

East Asian (EAS) AF: 0.828 AC: 32862 AN: 39700

South Asian (SAS) AF: 0.887 AC: 76531 AN: 86256

European-Finnish (FIN) AF: 0.797 AC: 42548 AN: 53374

Middle Eastern (MID) AF: 0.732 AC: 4223 AN: 5768

European-Non Finnish (NFE) AF: 0.752 AC: 836470 AN: 1111982

Other (OTH) AF: 0.779 AC: 47053 AN: 60390

GnomAD4 genome AF: 0.814 AC: 123888 AN: 152146 Hom.: 51135 Cov.: 32 AF XY: 0.817 AC XY: 60786 AN XY: 74364

African (AFR) AF: 0.952 AC: 39544 AN: 41528

American (AMR) AF: 0.719 AC: 11004 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2474 AN: 3470

East Asian (EAS) AF: 0.826 AC: 4253 AN: 5150

South Asian (SAS) AF: 0.895 AC: 4312 AN: 4820

European-Finnish (FIN) AF: 0.796 AC: 8427 AN: 10584

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51365 AN: 67984

Other (OTH) AF: 0.786 AC: 1662 AN: 2114

Alfa AF: 0.776 Hom.: 155965

Bravo AF: 0.811

TwinsUK AF: 0.746 AC: 2766

ALSPAC AF: 0.743 AC: 2865

ESP6500AA AF: 0.949 AC: 4183

ESP6500EA AF: 0.760 AC: 6539

ExAC AF: 0.791 AC: 96041

Asia WGS AF: 0.847 AC: 2945 AN: 3478

EpiCase AF: 0.761

EpiControl AF: 0.756

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephaly and chorioretinopathy 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.84
DANN	Benign	0.32
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.51	N
PhyloP100		0.80
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.040
Sift	Benign	0.69	T
Sift4G	Benign	0.56	T
Polyphen		0.0050	B
Vest4		0.063
MPC		0.15
ClinPred		0.0014	T
GERP RS		-5.7
Varity_R		0.013
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4838865; hg19: chr22-50664612; COSMIC: COSV107216501; COSMIC: COSV107216501;