NM_177987.3:c.600T>C

Variant names:

• chr10-47792-A-G
• rs148025238
• NM_177987.3:c.600T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_177987.3(TUBB8):​c.600T>C​(p.Phe200Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,596,546 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 36)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: TUBB8 NM_177987.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

Genes affected

TUBB8 (HGNC:20773): (tubulin beta 8 class VIII) The protein encoded by this gene represents the primary beta-tubulin subunit of oocytes and the early embryo. Defects in this gene, which is primate-specific, are a cause of oocyte maturation defect 2 and infertility. [provided by RefSeq, Mar 2016]

TUBB8 Gene-Disease associations (from GenCC):

• oocyte maturation defect 2

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00824 (1181/143252) while in subpopulation AFR AF = 0.0294 (1107/37702). AF 95% confidence interval is 0.0279. There are 7 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,SD,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177987.3. 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
	TUBB8	NM_177987.3	MANE Select	c.600T>C	p.Phe200Phe	synonymous	Exon 4 of 4	NP_817124.1
	TUBB8	NM_001389618.1		c.384T>C	p.Phe128Phe	synonymous	Exon 5 of 5	NP_001376547.1
	TUBB8	NM_001389619.1		c.384T>C	p.Phe128Phe	synonymous	Exon 5 of 5	NP_001376548.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB8	ENST00000568584.6	TSL:1 MANE Select	c.600T>C	p.Phe200Phe	synonymous	Exon 4 of 4	ENSP00000456206.2
	TUBB8	ENST00000564130.2	TSL:5	c.498T>C	p.Phe166Phe	synonymous	Exon 4 of 4	ENSP00000457610.1
	TUBB8	ENST00000568866.5	TSL:5	c.489T>C	p.Phe163Phe	synonymous	Exon 3 of 3	ENSP00000457062.1

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1181 AN: 143132 Hom.: 7 Cov.: 36

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.000600

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.000595

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000920

Gnomad OTH AF: 0.00777

GnomAD2 exomes AF: 0.00156 AC: 390 AN: 249742 AF XY: 0.00121

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000599 AC: 870 AN: 1453294 Hom.: 4 Cov.: 78 AF XY: 0.000517 AC XY: 374 AN XY: 723040

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

African (AFR) AF: 0.0221 AC: 731 AN: 33010

American (AMR) AF: 0.00105 AC: 46 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85818

European-Finnish (FIN) AF: 0.0000767 AC: 4 AN: 52138

Middle Eastern (MID) AF: 0.00146 AC: 8 AN: 5470

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1107532

Other (OTH) AF: 0.000967 AC: 58 AN: 59964

⚠️ 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 AF: 0.00824 AC: 1181 AN: 143252 Hom.: 7 Cov.: 36 AF XY: 0.00801 AC XY: 560 AN XY: 69886

African (AFR) AF: 0.0294 AC: 1107 AN: 37702

American (AMR) AF: 0.00293 AC: 42 AN: 14354

Ashkenazi Jewish (ASJ) AF: 0.000305 AC: 1 AN: 3280

East Asian (EAS) AF: 0.000601 AC: 3 AN: 4992

South Asian (SAS) AF: 0.000218 AC: 1 AN: 4590

European-Finnish (FIN) AF: 0.000595 AC: 6 AN: 10078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000921 AC: 6 AN: 65176

Other (OTH) AF: 0.00768 AC: 15 AN: 1952

Alfa AF: 0.00341 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.29
PhyloP100		1.4

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: rs148025238; hg19: chr10-93732; COSMIC: COSV59116339; COSMIC: COSV59116339;