rs1428191283

Variant names:

• chr1-202331921-C-T
• rs1428191283
• NM_014176.4:c.508G>A

Variant summary

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

The NM_014176.4(UBE2T):​c.508G>A​(p.Gly170Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G170V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE2T NM_014176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.789
• Publications: 0 publications found

Genes affected

UBE2T (HGNC:25009): (ubiquitin conjugating enzyme E2 T) The protein encoded by this gene catalyzes the covalent attachment of ubiquitin to protein substrates. Defects in this gene have been associated with Fanconi anemia of complementation group T. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

UBE2T Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group T

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.04639885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE2T	NM_014176.4	c.508G>A	p.Gly170Ser	missense_variant	Exon 7 of 7	ENST00000646651.1	NP_054895.1
UBE2T	NM_001310326.2	c.418G>A	p.Gly140Ser	missense_variant	Exon 7 of 7		NP_001297255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE2T	ENST00000646651.1	c.508G>A	p.Gly170Ser	missense_variant	Exon 7 of 7		NM_014176.4	ENSP00000494957.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 170 of the UBE2T protein (p.Gly170Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UBE2T-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.42
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.090	N;N
PhyloP100		-0.79
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.17	.;N
REVEL	Benign	0.024
Sift	Benign	0.38	.;T
Sift4G	Benign	0.78	.;T
Polyphen		0.0	B;B
Vest4		0.062
MutPred		0.16		Gain of phosphorylation at G170 (P = 0.0279);Gain of phosphorylation at G170 (P = 0.0279);
MVP		0.29
MPC		0.15
ClinPred		0.022	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.019
gMVP		0.15
Mutation Taster		=99/1	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: rs1428191283; hg19: chr1-202301049;