NM_020461.4:c.1118C>T

Variant names:

• chr22-50229576-G-A
• rs34273213
• NM_020461.4:c.1118C>T

Variant summary

Our verdict is Benign. The variant received -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. 17/23 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
• 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), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1118C>T	p.Pro373Leu	missense splice_region	Exon 4 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.1118C>T	p.Pro373Leu	missense splice_region	Exon 4 of 25	ENSP00000248846.5
	TUBGCP6	ENST00000439308.7	TSL:1	n.1118C>T		splice_region non_coding_transcript_exon	Exon 4 of 25	ENSP00000397387.2
	TUBGCP6	ENST00000498611.5	TSL:1	n.1651C>T		splice_region non_coding_transcript_exon	Exon 4 of 23

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

GnomAD2 exomes AF: 0.000832 AC: 166 AN: 199514 AF XY: 0.000584

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 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

African (AFR) AF: 0.0129 AC: 424 AN: 32750

American (AMR) AF: 0.000733 AC: 30 AN: 40926

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25666

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37982

South Asian (SAS) AF: 0.00 AC: 0 AN: 82438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5074

European-Non Finnish (NFE) AF: 0.0000400 AC: 44 AN: 1098968

Other (OTH) AF: 0.000574 AC: 34 AN: 59254

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

African (AFR) AF: 0.0109 AC: 453 AN: 41548

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00142 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N
PhyloP100		0.20
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.052
Sift	Benign	0.38	T
Sift4G	Benign	0.18	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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs34273213; hg19: chr22-50668005;