1-110112716-T-C

Variant names:

• chr1-110112716-T-C
• rs759511338
• NM_203412.2:c.182T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203412.2(UBL4B):​c.182T>C​(p.Ile61Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: UBL4B NM_203412.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.927

Genes affected

UBL4B (HGNC:32309): (ubiquitin like 4B) Involved in positive regulation of protein targeting to mitochondrion. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBL4B	NM_203412.2	c.182T>C	p.Ile61Thr	missense_variant	Exon 1 of 1	ENST00000334179.5	NP_981957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBL4B	ENST00000334179.5	c.182T>C	p.Ile61Thr	missense_variant	Exon 1 of 1	6	NM_203412.2	ENSP00000334044.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182T>C (p.I61T) alteration is located in exon 1 (coding exon 1) of the UBL4B gene. This alteration results from a T to C substitution at nucleotide position 182, causing the isoleucine (I) at amino acid position 61 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.094
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.63	P
Vest4		0.62
MutPred		0.77		Loss of stability (P = 0.0326);
MVP		0.76
MPC		0.44
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.45
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs759511338; hg19: chr1-110655338;