19-4446537-G-A

Variant names:

• chr19-4446537-G-A
• NM_025241.3:c.883C>T

Variant summary

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

The NM_025241.3(UBXN6):​c.883C>T​(p.Leu295Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UBXN6 NM_025241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32
• Publications: 0 publications found

Genes affected

UBXN6 (HGNC:14928): (UBX domain protein 6) Involved in ERAD pathway; endosome to lysosome transport via multivesicular body sorting pathway; and macroautophagy. Located in bounding membrane of organelle and cytosol. Is extrinsic component of membrane. Part of endosome and protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

CHAF1A (HGNC:1910): (chromatin assembly factor 1 subunit A) Chromatin assembly factor I (CAF1) is a nuclear complex consisting of p50, p60 (CHAF1B; MIM 601245), and p150 (CHAF1A) subunits that assembles histone octamers onto replicating DNA in vitro (Kaufman et al., 1995 [PubMed 7600578]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025241.3. 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
	UBXN6	NM_025241.3	MANE Select	c.883C>T	p.Leu295Phe	missense	Exon 8 of 11	NP_079517.1	Q9BZV1-1
	UBXN6	NM_001171091.2		c.724C>T	p.Leu242Phe	missense	Exon 8 of 11	NP_001164562.1	Q9BZV1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBXN6	ENST00000301281.11	TSL:1 MANE Select	c.883C>T	p.Leu295Phe	missense	Exon 8 of 11	ENSP00000301281.5	Q9BZV1-1
	UBXN6	ENST00000394765.7	TSL:1	c.724C>T	p.Leu242Phe	missense	Exon 8 of 11	ENSP00000378246.2	Q9BZV1-2
	UBXN6	ENST00000950415.1		c.985C>T	p.Leu329Phe	missense	Exon 8 of 11	ENSP00000620474.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459734 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726250

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.29		Gain of phosphorylation at T296 (P = 0.2077)
MVP		0.76
MPC		0.33
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.53
Mutation Taster		=19/81	disease causing

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: chr19-4446534;