NM_201402.3:c.1498G>A

Variant names:

• chr8-12137263-C-T
• rs199889083
• NM_201402.3:c.1498G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_201402.3(USP17L2):​c.1498G>A​(p.Val500Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,528,980 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (68 hom.)
• Consequence: USP17L2 NM_201402.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07
• Publications: 2 publications found

Genes affected

USP17L2 (HGNC:34434): (ubiquitin specific peptidase 17 like family member 2) DUB3 is a member of the ubiquitin processing protease (UBP) subfamily of deubiquitinating enzymes. See USP1 (MIM 603478) for background information.[supplied by OMIM, Mar 2008]

FAM66D (HGNC:24159): (family with sequence similarity 66 member D)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005227953).
• BP6: Variant 8-12137263-C-T is Benign according to our data. Variant chr8-12137263-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2658423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201402.3. 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
	USP17L2	NM_201402.3	MANE Select	c.1498G>A	p.Val500Met	missense	Exon 1 of 1	NP_958804.2	Q6R6M4
	FAM66D	NR_027425.1		n.609-8160C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP17L2	ENST00000333796.4	TSL:6 MANE Select	c.1498G>A	p.Val500Met	missense	Exon 1 of 1	ENSP00000333329.3	Q6R6M4
	FAM66D	ENST00000434078.3	TSL:5	n.545-8376C>T		intron	N/A
	FAM66D	ENST00000653269.1		n.706-8160C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 386 AN: 140148 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000468

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000910

Gnomad OTH AF: 0.00207

GnomAD2 exomes AF: 0.000867 AC: 199 AN: 229644 AF XY: 0.000685

Gnomad AFR exome AF: 0.00756

Gnomad AMR exome AF: 0.000340

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.000194

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.000874

GnomAD4 exome AF: 0.00108 AC: 1496 AN: 1388740 Hom.: 68 Cov.: 35 AF XY: 0.00102 AC XY: 701 AN XY: 689806

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

African (AFR) AF: 0.00789 AC: 243 AN: 30812

American (AMR) AF: 0.000571 AC: 24 AN: 42030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.000976 AC: 33 AN: 33822

South Asian (SAS) AF: 0.0000388 AC: 3 AN: 77256

European-Finnish (FIN) AF: 0.000140 AC: 7 AN: 50062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3876

European-Non Finnish (NFE) AF: 0.00105 AC: 1123 AN: 1068846

Other (OTH) AF: 0.00111 AC: 63 AN: 56980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00276 AC: 387 AN: 140240 Hom.: 30 Cov.: 33 AF XY: 0.00235 AC XY: 160 AN XY: 68040

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

African (AFR) AF: 0.00826 AC: 307 AN: 37158

American (AMR) AF: 0.00102 AC: 14 AN: 13790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.000704 AC: 3 AN: 4264

South Asian (SAS) AF: 0.00 AC: 0 AN: 4022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.000910 AC: 59 AN: 64812

Other (OTH) AF: 0.00205 AC: 4 AN: 1954

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00158 Hom.: 1

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00635 AC: 18

ESP6500EA AF: 0.00117 AC: 7

ExAC AF: 0.00114 AC: 127

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.1
DANN	Benign	0.39
DEOGEN2	Benign	0.00092	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00014	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.012
Sift	Benign	0.50	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.061
MVP		0.13
MPC		0.37
ClinPred		0.00073	T
GERP RS		-0.84
Varity_R		0.044
gMVP		0.019
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs199889083; hg19: chr8-11994772; COSMIC: COSV99074556; COSMIC: COSV99074556;