chr19-4446381-C-A

Variant names:

• chr19-4446381-C-A
• rs781219649
• NM_025241.3:c.953G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025241.3(UBXN6):​c.953G>T​(p.Arg318Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBXN6 NM_025241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBXN6	NM_025241.3	c.953G>T	p.Arg318Leu	missense_variant	Exon 9 of 11	ENST00000301281.11	NP_079517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBXN6	ENST00000301281.11	c.953G>T	p.Arg318Leu	missense_variant	Exon 9 of 11	1	NM_025241.3	ENSP00000301281.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424550 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.87	P;D
Vest4		0.91
MutPred		0.49		Loss of disorder (P = 0.0362);.;
MVP		0.70
MPC		0.25
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs781219649; hg19: chr19-4446378;