Genetic Variant NM_014688.5:c.2399C>T (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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014688.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP6NL	NM_014688.5	MANE Select	c.2399C>T	p.Ser800Phe	missense	Exon 15 of 15	NP_055503.1	Q92738-1
USP6NL	NM_001391959.1		c.2468C>T	p.Ser823Phe	missense	Exon 14 of 14	NP_001378888.1	X6RAB3
USP6NL	NM_001080491.5		c.2450C>T	p.Ser817Phe	missense	Exon 14 of 14	NP_001073960.1	Q92738-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP6NL	ENST00000609104.6	TSL:1 MANE Select	c.2399C>T	p.Ser800Phe	missense	Exon 15 of 15	ENSP00000476462.1	Q92738-1
USP6NL	ENST00000938640.1		c.2519C>T	p.Ser840Phe	missense	Exon 17 of 17	ENSP00000608699.1
USP6NL	ENST00000938639.1		c.2477C>T	p.Ser826Phe	missense	Exon 16 of 16	ENSP00000608698.1

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.0015

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0055

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

PhyloP100

4.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.95

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.059

Polyphen

0.47

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over