chr19-4446301-C-A

Variant names:

• chr19-4446301-C-A
• rs556207850
• NM_025241.3:c.1033G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025241.3(UBXN6):​c.1033G>T​(p.Asp345Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,418,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBXN6 NM_025241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

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.1033G>T	p.Asp345Tyr	missense	Exon 9 of 11	NP_079517.1	Q9BZV1-1
	UBXN6	NM_001171091.2		c.874G>T	p.Asp292Tyr	missense	Exon 9 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.1033G>T	p.Asp345Tyr	missense	Exon 9 of 11	ENSP00000301281.5	Q9BZV1-1
	UBXN6	ENST00000394765.7	TSL:1	c.874G>T	p.Asp292Tyr	missense	Exon 9 of 11	ENSP00000378246.2	Q9BZV1-2
	UBXN6	ENST00000950415.1		c.1135G>T	p.Asp379Tyr	missense	Exon 9 of 11	ENSP00000620474.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703404

African (AFR) AF: 0.00 AC: 0 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 39908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24966

East Asian (EAS) AF: 0.00 AC: 0 AN: 38354

South Asian (SAS) AF: 0.00 AC: 0 AN: 82296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095278

Other (OTH) AF: 0.00 AC: 0 AN: 58882

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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.82		Gain of MoRF binding (P = 0.0364)
MVP		0.80
MPC		0.34
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.95
gMVP		0.92
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs556207850; hg19: chr19-4446298;