rs12539800

Variant names:

• chr7-129839298-T-A
• rs12539800
• NM_003344.4:c.336A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-129839298-T-A
• chr7-129839298-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003344.4(UBE2H):​c.336A>T​(p.Leu112Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L112L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UBE2H NM_003344.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

UBE2H (HGNC:12484): (ubiquitin conjugating enzyme E2 H) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. The encoded protein sequence is 100% identical to the mouse homolog and 98% identical to the frog and zebrafish homologs. Three alternatively spliced transcript variants have been found for this gene and they encode distinct isoforms. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE2H	NM_003344.4	c.336A>T	p.Leu112Phe	missense_variant	Exon 6 of 7	ENST00000355621.8	NP_003335.1
UBE2H	NM_182697.3	c.243A>T	p.Leu81Phe	missense_variant	Exon 4 of 5		NP_874356.1
UBE2H	NM_001202498.2	c.126A>T	p.Leu42Phe	missense_variant	Exon 6 of 7		NP_001189427.1
UBE2H	XM_047420796.1	c.126A>T	p.Leu42Phe	missense_variant	Exon 7 of 8		XP_047276752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE2H	ENST00000355621.8	c.336A>T	p.Leu112Phe	missense_variant	Exon 6 of 7	1	NM_003344.4	ENSP00000347836.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461690 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.9	H;.;.;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.9	D;.;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.024	D;.;D;D
Sift4G	Uncertain	0.014	D;.;D;.
Polyphen		0.77	P;.;.;.
Vest4		0.78
MutPred		0.79		Gain of catalytic residue at P110 (P = 0.1701);.;.;.;
MVP		0.94
MPC		3.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.66
gMVP		0.99
Mutation Taster		=10/90	disease causing

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: rs12539800; hg19: chr7-129479138;