4-67630474-C-A

Variant names:

• chr4-67630474-C-A
• rs2109900661
• NM_018227.6:c.2320G>T

Variant summary

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

The NM_018227.6(UBA6):​c.2320G>T​(p.Ala774Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,433,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A774T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBA6 NM_018227.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• Publications: 0 publications found

Genes affected

UBA6 (HGNC:25581): (ubiquitin like modifier activating enzyme 6) Modification of proteins with ubiquitin (UBB; MIM 191339) or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin-activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3). UBE1L2 is an E1 enzyme that initiates the activation and conjugation of ubiquitin-like proteins (Jin et al., 2007 [PubMed 17597759]).[supplied by OMIM, Mar 2008]

UBA6 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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=0.032942027).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018227.6. 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
	UBA6	NM_018227.6	MANE Select	c.2320G>T	p.Ala774Ser	missense	Exon 26 of 33	NP_060697.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA6	ENST00000322244.10	TSL:1 MANE Select	c.2320G>T	p.Ala774Ser	missense	Exon 26 of 33	ENSP00000313454.4	A0AVT1-1
	UBA6	ENST00000907530.1		c.2338G>T	p.Ala780Ser	missense	Exon 27 of 34	ENSP00000577589.1
	UBA6	ENST00000907528.1		c.2326G>T	p.Ala776Ser	missense	Exon 26 of 33	ENSP00000577587.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1433822 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 711362

African (AFR) AF: 0.00 AC: 0 AN: 32768

American (AMR) AF: 0.00 AC: 0 AN: 41280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00 AC: 0 AN: 81714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097388

Other (OTH) AF: 0.0000169 AC: 1 AN: 59174

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.90
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.41		Loss of loop (P = 0.0512)
MVP		0.043
MPC		0.13
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.020
gMVP		0.10
Mutation Taster		=93/7	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: rs2109900661; hg19: chr4-68496192;