1-235433057-A-G

Variant names:

• chr1-235433057-A-G
• rs750026092
• NM_003193.5:c.661-1147A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001287801.2(TBCE):​c.772A>G​(p.Ser258Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,553,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TBCE NM_001287801.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0640
• Publications: 0 publications found

Genes affected

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000285053 (HGNC:):

RPS21P1 (HGNC:36401): (ribosomal protein S21 pseudogene 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0647966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287801.2. 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
	TBCE	NM_003193.5	MANE Select	c.661-1147A>G		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.772A>G	p.Ser258Gly	missense	Exon 8 of 18	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.661-1147A>G		intron	N/A	NP_001072983.1	Q15813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.661-1147A>G		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.661-1147A>G		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.472-1147A>G		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000665 AC: 11 AN: 165396 AF XY: 0.0000989

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.0000200 AC: 28 AN: 1401018 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 19 AN XY: 693826

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 37714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 36994

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79132

European-Finnish (FIN) AF: 0.0000564 AC: 2 AN: 35466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5382

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090242

Other (OTH) AF: 0.0000852 AC: 5 AN: 58688

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000346 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive Kenny-Caffey syndrome;C1855840:Hypoparathyroidism-retardation-dysmorphism syndrome;C4310667:Encephalopathy, progressive, with amyotrophy and optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.4
DANN	Benign	0.70
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.064
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.10
Sift	Benign	0.085	T
Sift4G	Benign	0.65	T
Vest4		0.053
MutPred		0.48		Loss of stability (P = 0.0584)
MVP		0.17
ClinPred		0.071	T
GERP RS		-1.2
gMVP		0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750026092; hg19: chr1-235596372;