4-67622894-A-G

Variant names:

• chr4-67622894-A-G
• NM_018227.6:c.2960T>C

Variant summary

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

The NM_018227.6(UBA6):​c.2960T>C​(p.Val987Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBA6 NM_018227.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• 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.2960T>C	p.Val987Ala	missense_variant	Exon 32 of 33	ENST00000322244.10	NP_060697.4
UBA6	XM_017008359.3	c.2960T>C	p.Val987Ala	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.2960T>C	p.Val987Ala	missense_variant	Exon 32 of 33	1	NM_018227.6	ENSP00000313454.4
UBA6	ENST00000514261.1	n.*15T>C		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000425091.1
UBA6	ENST00000514261.1	n.*15T>C		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000425091.1

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 specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2960T>C (p.V987A) alteration is located in exon 32 (coding exon 32) of the UBA6 gene. This alteration results from a T to C substitution at nucleotide position 2960, causing the valine (V) at amino acid position 987 to be replaced by an alanine (A). 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.19
Sift	Benign	0.36	T
Sift4G	Benign	0.49	T
Polyphen		0.063	B
Vest4		0.86
MutPred		0.63		Loss of sheet (P = 0.0315);
MVP		0.26
MPC		0.19
ClinPred		0.83	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.56
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

hg19: chr4-68488612;