NM_025241.3:c.1090G>C

Variant names:

• chr19-4446159-C-G
• rs775713602
• NM_025241.3:c.1090G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025241.3(UBXN6):​c.1090G>C​(p.Gly364Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G364W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBXN6 NM_025241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.968
• 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]

MIR4746 (HGNC:41904): (microRNA 4746) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15216121).

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.1090G>C	p.Gly364Arg	missense	Exon 10 of 11	NP_079517.1	Q9BZV1-1
	UBXN6	NM_001171091.2		c.931G>C	p.Gly311Arg	missense	Exon 10 of 11	NP_001164562.1	Q9BZV1-2
	MIR4746	NR_039901.1		n.*111C>G		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBXN6	ENST00000301281.11	TSL:1 MANE Select	c.1090G>C	p.Gly364Arg	missense	Exon 10 of 11	ENSP00000301281.5	Q9BZV1-1
	UBXN6	ENST00000394765.7	TSL:1	c.931G>C	p.Gly311Arg	missense	Exon 10 of 11	ENSP00000378246.2	Q9BZV1-2
	UBXN6	ENST00000950415.1		c.1192G>C	p.Gly398Arg	missense	Exon 10 of 11	ENSP00000620474.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457560 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725230

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111440

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.5
DANN	Benign	0.63
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.97
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.029
Sift	Benign	0.44	T
Sift4G	Benign	0.34	T
Polyphen		0.0070	B
Vest4		0.23
MutPred		0.50		Gain of MoRF binding (P = 0.0307)
MVP		0.29
MPC		0.052
ClinPred		0.072	T
GERP RS		-1.7
Varity_R		0.044
gMVP		0.42
Mutation Taster		=95/5	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

dbSNP: rs775713602; hg19: chr19-4446156;