10-11463309-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014688.5(USP6NL):​c.1619A>T​(p.Glu540Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

USP6NL
NM_014688.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42
Variant links:
Genes affected
USP6NL (HGNC:16858): (USP6 N-terminal like) Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including plasma membrane to endosome transport; positive regulation of GTPase activity; and retrograde transport, plasma membrane to Golgi. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12538126).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP6NLNM_014688.5 linkuse as main transcriptc.1619A>T p.Glu540Val missense_variant 15/15 ENST00000609104.6 NP_055503.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP6NLENST00000609104.6 linkuse as main transcriptc.1619A>T p.Glu540Val missense_variant 15/151 NM_014688.5 ENSP00000476462 P1Q92738-1
USP6NLENST00000379237.6 linkuse as main transcriptc.1688A>T p.Glu563Val missense_variant 14/145 ENSP00000368539
USP6NLENST00000277575.5 linkuse as main transcriptc.1670A>T p.Glu557Val missense_variant 14/145 ENSP00000277575 Q92738-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249092
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135164
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461630
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00142
Bravo
AF:
0.00000756
Asia WGS
AF:
0.00404
AC:
14
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2023The c.1670A>T (p.E557V) alteration is located in exon 14 (coding exon 14) of the USP6NL gene. This alteration results from a A to T substitution at nucleotide position 1670, causing the glutamic acid (E) at amino acid position 557 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
0.14
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.092
T;.;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.53
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N;.;.
MutationTaster
Benign
0.90
N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.5
.;N;.
REVEL
Benign
0.035
Sift
Uncertain
0.0020
.;D;.
Sift4G
Uncertain
0.057
T;T;T
Polyphen
0.34
B;B;.
Vest4
0.12
MutPred
0.18
Gain of MoRF binding (P = 0.0289);.;.;
MVP
0.43
MPC
0.18
ClinPred
0.22
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.26

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs981085886; hg19: chr10-11505308; API