22-50220827-T-C

Variant names:

• chr22-50220827-T-C
• rs1215314321
• NM_020461.4:c.3532A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020461.4(TUBGCP6):​c.3532A>G​(p.Met1178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1178L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 27)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBGCP6 NM_020461.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0290
• Publications: 1 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), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017602265).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	NM_020461.4	MANE Select	c.3532A>G	p.Met1178Val	missense	Exon 16 of 25	NP_065194.3	Q96RT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.3532A>G	p.Met1178Val	missense	Exon 16 of 25	ENSP00000248846.5	Q96RT7-1
	TUBGCP6	ENST00000439308.7	TSL:1	n.3532A>G		non_coding_transcript_exon	Exon 16 of 25	ENSP00000397387.2	E7EQL8
	TUBGCP6	ENST00000498611.5	TSL:1	n.3617+448A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 125 AN: 84186 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00251

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.000894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000969

Gnomad OTH AF: 0.00247

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229718 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000937

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.76e-7 AC: 1 AN: 1289200 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 641196

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27882

American (AMR) AF: 0.0000276 AC: 1 AN: 36266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19226

East Asian (EAS) AF: 0.00 AC: 0 AN: 23908

South Asian (SAS) AF: 0.00 AC: 0 AN: 83102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4912

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003384

Other (OTH) AF: 0.00 AC: 0 AN: 48566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00148 AC: 125 AN: 84250 Hom.: 0 Cov.: 27 AF XY: 0.00133 AC XY: 55 AN XY: 41296

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00229 AC: 50 AN: 21796

American (AMR) AF: 0.00207 AC: 17 AN: 8196

Ashkenazi Jewish (ASJ) AF: 0.000894 AC: 2 AN: 2236

East Asian (EAS) AF: 0.00 AC: 0 AN: 2290

South Asian (SAS) AF: 0.00127 AC: 3 AN: 2364

European-Finnish (FIN) AF: 0.00205 AC: 9 AN: 4392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.000969 AC: 40 AN: 41270

Other (OTH) AF: 0.00245 AC: 3 AN: 1226

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0599 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.040
DANN	Benign	0.48
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.042	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.7	N
PhyloP100		0.029
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.26		Loss of helix (P = 0.1299)
MVP		0.072
MPC		0.11
ClinPred		0.030	T
GERP RS		1.2
PromoterAI		-0.018	Neutral
Varity_R		0.023
gMVP		0.14
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1215314321; hg19: chr22-50659256;