19-36121691-C-A

Variant names:

• chr19-36121691-C-A
• rs1425374917
• NM_001281.3:c.520C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001281.3(TBCB):​c.520C>A​(p.Pro174Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P174A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TBCB NM_001281.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• Publications: 0 publications found

Genes affected

TBCB (HGNC:1989): (tubulin folding cofactor B) Predicted to be involved in cell differentiation and nervous system development. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038559735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281.3. 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
	TBCB	NM_001281.3	MANE Select	c.520C>A	p.Pro174Thr	missense	Exon 4 of 6	NP_001272.2	Q99426-1
	TBCB	NM_001300971.3		c.367C>A	p.Pro123Thr	missense	Exon 4 of 6	NP_001287900.1	Q99426-2
	TBCB	NR_155756.2		n.1114C>A		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCB	ENST00000221855.8	TSL:1 MANE Select	c.520C>A	p.Pro174Thr	missense	Exon 4 of 6	ENSP00000221855.3	Q99426-1
	TBCB	ENST00000588385.5	TSL:1	c.367C>A	p.Pro123Thr	missense	Exon 3 of 5	ENSP00000467172.1	K7EP07
	TBCB	ENST00000651435.1		c.520C>A	p.Pro174Thr	missense	Exon 4 of 7	ENSP00000498740.1	A0A494C0X0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402786 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 692642

⚠️ 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: 31986

American (AMR) AF: 0.00 AC: 0 AN: 36916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24230

East Asian (EAS) AF: 0.00 AC: 0 AN: 36588

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082700

Other (OTH) AF: 0.00 AC: 0 AN: 57864

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.3
DANN	Benign	0.093
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.64
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.14
Sift	Benign	0.74	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.032
MutPred		0.27		Gain of phosphorylation at P174 (P = 0.029)
MVP		0.57
MPC		0.62
ClinPred		0.052	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.19
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1425374917; hg19: chr19-36612593;