Genetic Variant USP6NL:p.Ser800Phe (chr10-11462529-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014688.5(USP6NL):c.2399C>T(p.Ser800Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 1 hom. )

Consequence

USP6NL
NM_014688.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.41

Publications

4 publications found

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]

USP6NL links:

ENSG00000301463 (HGNC:):

ENSG00000301463 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27293336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP6NL	NM_014688.5 link	c.2399C>T	p.Ser800Phe	missense_variant	Exon 15 of 15	ENST00000609104.6	NP_055503.1	Q92738-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP6NL	ENST00000609104.6 link	c.2399C>T	p.Ser800Phe	missense_variant	Exon 15 of 15	1	NM_014688.5	ENSP00000476462.1		Q92738-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111870

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2450C>T (p.S817F) alteration is located in exon 14 (coding exon 14) of the USP6NL gene. This alteration results from a C to T substitution at nucleotide position 2450, causing the serine (S) at amino acid position 817 to be replaced by a phenylalanine (F). 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

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

T;.;.

Eigen

Benign

-0.0015

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0055

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;.;.

PhyloP100

4.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.95

.;N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.059

T;T;T

Polyphen

0.47

P;P;.

Vest4

0.14

MutPred

0.28

Loss of glycosylation at S800 (P = 1e-04);.;.;

MVP

0.64

MPC

0.29

ClinPred

0.44

GERP RS

6.0

Varity_R

0.16

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

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

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chr10-11462529-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over