19-4445562-G-A

Variant names:

• chr19-4445562-G-A
• rs77077573
• NM_025241.3:c.1262C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025241.3(UBXN6):​c.1262C>T​(p.Ala421Val) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: UBXN6 NM_025241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07768616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBXN6	NM_025241.3	c.1262C>T	p.Ala421Val	missense_variant	Exon 11 of 11	ENST00000301281.11	NP_079517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBXN6	ENST00000301281.11	c.1262C>T	p.Ala421Val	missense_variant	Exon 11 of 11	1	NM_025241.3	ENSP00000301281.5

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000329 AC: 82 AN: 248956 AF XY: 0.000341

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000348 AC: 509 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 254 AN XY: 727062

Gnomad4 AFR exome AF: 0.000149 AC: 5 AN: 33478

Gnomad4 AMR exome AF: 0.000201 AC: 9 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86258

Gnomad4 FIN exome AF: 0.000226 AC: 12 AN: 53062

Gnomad4 NFE exome AF: 0.000418 AC: 465 AN: 1111980

Gnomad4 Remaining exome AF: 0.000265 AC: 16 AN: 60382

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74504

Gnomad4 AFR AF: 0.0000962 AC: 0.000096177 AN: 0.000096177

Gnomad4 AMR AF: 0.000131 AC: 0.000130685 AN: 0.000130685

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000940911 AN: 0.0000940911

Gnomad4 NFE AF: 0.000617 AC: 0.000617447 AN: 0.000617447

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1262C>T (p.A421V) alteration is located in exon 11 (coding exon 11) of the UBXN6 gene. This alteration results from a C to T substitution at nucleotide position 1262, causing the alanine (A) at amino acid position 421 to be replaced by a valine (V). 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	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;P
Vest4		0.25
MVP		0.71
MPC		0.25
ClinPred		0.11	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.51
Mutation Taster		=83/17	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

Publications

LitVar

Other links and lift over

dbSNP: rs77077573; hg19: chr19-4445559; COSMIC: COSV56673343; COSMIC: COSV56673343;