dbSNP rs4713354: TUBB:c.-160+4A>C (chr6-30717643-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000681435.1(TUBB):c.-160+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,232 control chromosomes in the GnomAD database, including 5,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 5585 hom., cov: 33)

Exomes 𝑓: 0.19 ( 0 hom. )

Consequence

TUBB
ENST00000681435.1 splice_region, intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.970

Publications

27 publications found

Variant links:

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB links:

MDC1 (HGNC:21163): (mediator of DNA damage checkpoint 1) The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]

MDC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000681435.1 link	c.-160+4A>C		splice_region_variant, intron_variant	Intron 1 of 3			ENSP00000506665.1		Q5ST81
MDC1	ENST00000425072.5 link	c.-398T>G		upstream_gene_variant		3		ENSP00000396989.1		A2AB07

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32830

AN:

152080

Hom.:

5565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.0403

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.245

GnomAD4 exome

AF:

0.188

AC:

AN:

Hom.:

Cov.:

AF XY:

0.200

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.150

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.200

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.216

AC:

32890

AN:

152200

Hom.:

5585

Cov.:

AF XY:

0.212

AC XY:

15790

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.468

AC:

19438

AN:

41494

American (AMR)

AF:

0.207

AC:

3170

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

553

AN:

3470

East Asian (EAS)

AF:

0.174

AC:

901

AN:

5182

South Asian (SAS)

AF:

0.188

AC:

906

AN:

4830

European-Finnish (FIN)

AF:

0.0403

AC:

427

AN:

10608

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.101

AC:

6858

AN:

68002

Other (OTH)

AF:

0.247

AC:

523

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1154

2308

3463

4617

5771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.168

Hom.:

6290

Bravo

AF:

0.242

Asia WGS

AF:

0.243

AC:

845

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.0

(source)

DANN

Benign

0.61

PhyloP100

-0.97

PromoterAI

-0.13

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over