22-50220827-T-A

Variant names:

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

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>T​(p.Met1178Leu) 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. M1178V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0 (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=0.044837803).

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>T	p.Met1178Leu	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>T	p.Met1178Leu	missense	Exon 16 of 25	ENSP00000248846.5	Q96RT7-1
	TUBGCP6	ENST00000439308.7	TSL:1	n.3532A>T		non_coding_transcript_exon	Exon 16 of 25	ENSP00000397387.2	E7EQL8
	TUBGCP6	ENST00000498611.5	TSL:1	n.3617+448A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000473 AC: 4 AN: 84610 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000435

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.000225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1289282 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 641220

African (AFR) AF: 0.00 AC: 0 AN: 27886

American (AMR) AF: 0.00 AC: 0 AN: 36292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19240

East Asian (EAS) AF: 0.00 AC: 0 AN: 23918

South Asian (SAS) AF: 0.00 AC: 0 AN: 83122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41956

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: 48572

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000590 AC: 5 AN: 84678 Hom.: 0 Cov.: 27 AF XY: 0.0000964 AC XY: 4 AN XY: 41498

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

African (AFR) AF: 0.0000455 AC: 1 AN: 21964

American (AMR) AF: 0.000121 AC: 1 AN: 8232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2244

East Asian (EAS) AF: 0.000436 AC: 1 AN: 2296

South Asian (SAS) AF: 0.000421 AC: 1 AN: 2376

European-Finnish (FIN) AF: 0.000225 AC: 1 AN: 4436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41412

Other (OTH) AF: 0.00 AC: 0 AN: 1228

⚠️ 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.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.8
DANN	Benign	0.65
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.059	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.029
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.015
Sift	Benign	0.38	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.32		Gain of helix (P = 0.1736)
MVP		0.11
MPC		0.10
ClinPred		0.022	T
GERP RS		1.2
PromoterAI		-0.024	Neutral
Varity_R		0.039
gMVP		0.19
Mutation Taster		=94/6	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;