Genetic Variant USP17L8:p.Pro25Pro (chr8-7973179-T-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001256872.1(USP17L8):c.75A>T(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0013 ( 15 hom. )

Failed GnomAD Quality Control

Consequence

USP17L8
NM_001256872.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.524

Publications

2 publications found

Variant links:

Genes affected

USP17L8 (HGNC:37181): (ubiquitin specific peptidase 17 like family member 8) Predicted to enable cysteine-type endopeptidase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein deubiquitination and regulation of apoptotic process. Predicted to be located in endoplasmic reticulum. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

USP17L8 links:

LOC124901865 (HGNC:):

LOC124901865 links:

FAM66E (HGNC:18735): (family with sequence similarity 66 member E)

FAM66E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 8-7973179-T-A is Benign according to our data. Variant chr8-7973179-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2658366.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.524 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 15 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256872.1. 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
	USP17L8	NM_001256872.1	MANE Select	c.75A>T	p.Pro25Pro	synonymous	Exon 1 of 1	NP_001243801.1	P0C7I0
	FAM66E	NR_027424.1		n.610+11883T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP17L8	ENST00000527080.1	TSL:6 MANE Select	c.75A>T	p.Pro25Pro	synonymous	Exon 1 of 1	ENSP00000485306.1	P0C7I0
FAM66E	ENST00000529252.2	TSL:2	n.609+11883T>A		intron	N/A
FAM66E	ENST00000533615.1	TSL:2	n.1154-11086T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

23616

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000991

AC:

AN:

23218

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.000334

Gnomad ASJ exome

AF:

0.00463

Gnomad EAS exome

AF:

0.000902

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000942

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00127

AC:

104

AN:

81610

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

AN XY:

42800

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00132

AC:

AN:

20412

American (AMR)

AF:

0.000586

AC:

AN:

5116

Ashkenazi Jewish (ASJ)

AF:

0.00768

AC:

AN:

912

East Asian (EAS)

AF:

0.000419

AC:

AN:

4772

South Asian (SAS)

AF:

0.000943

AC:

AN:

11666

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

1960

Middle Eastern (MID)

AF:

0.00789

AC:

AN:

380

European-Non Finnish (NFE)

AF:

0.00117

AC:

AN:

30664

Other (OTH)

AF:

0.00227

AC:

AN:

5728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000157763), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.361

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

23616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

11032

African (AFR)

AF:

0.00

AC:

AN:

21480

American (AMR)

AF:

0.00

AC:

AN:

870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

168

South Asian (SAS)

AF:

0.00

AC:

AN:

158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

680

Other (OTH)

AF:

0.00

AC:

AN:

224

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

7.8

(source)

DANN

Benign

0.35

PhyloP100

-0.52

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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