NM_018227.6:c.2936A>T

Variant names:

• chr4-67622918-T-A
• rs749576540
• NM_018227.6:c.2936A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018227.6(UBA6):​c.2936A>T​(p.Tyr979Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y979C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBA6 NM_018227.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA6	NM_018227.6	c.2936A>T	p.Tyr979Phe	missense_variant	Exon 32 of 33	ENST00000322244.10	NP_060697.4
UBA6	XM_017008359.3	c.2936A>T	p.Tyr979Phe	missense_variant	Exon 32 of 33		XP_016863848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA6	ENST00000322244.10	c.2936A>T	p.Tyr979Phe	missense_variant	Exon 32 of 33	1	NM_018227.6	ENSP00000313454.4
UBA6	ENST00000514261.1	n.258A>T		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000425091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455332 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723776

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.00 AC: 0 AN: 43590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109276

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Benign	0.040	D
Sift4G	Benign	0.095	T
Polyphen		0.93	P
Vest4		0.65
MutPred		0.63		Loss of sheet (P = 0.0126);
MVP		0.23
MPC		0.28
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.50
gMVP		0.48
Mutation Taster		=68/32	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: rs749576540; hg19: chr4-68488636;