8-12133977-G-T

Variant names:

• chr8-12133977-G-T
• rs760391238
• NM_001256869.2:c.33C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001256869.2(USP17L7):​c.33C>A​(p.Asp11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,147,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000011 (1 hom.)
• Consequence: USP17L7 NM_001256869.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 0 publications found

Genes affected

USP17L7 (HGNC:37180): (ubiquitin specific peptidase 17 like family member 7) 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040902823).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256869.2. 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
	USP17L7	NM_001256869.2	MANE Select	c.33C>A	p.Asp11Glu	missense	Exon 1 of 1	NP_001243798.1	P0C7H9
	FAM66D	NR_027425.1		n.609-11446G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP17L7	ENST00000530447.5	TSL:6 MANE Select	c.33C>A	p.Asp11Glu	missense	Exon 1 of 1	ENSP00000485337.2	P0C7H9
	FAM66D	ENST00000434078.3	TSL:5	n.545-11662G>T		intron	N/A
	FAM66D	ENST00000653269.1		n.706-11446G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144456 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000141

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: 0.0000351 AC: 8 AN: 227992 AF XY: 0.0000240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000286

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 11 AN: 1002674 Hom.: 1 Cov.: 18 AF XY: 0.0000117 AC XY: 6 AN XY: 514548

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

African (AFR) AF: 0.00 AC: 0 AN: 25828

American (AMR) AF: 0.000141 AC: 6 AN: 42588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22764

East Asian (EAS) AF: 0.00 AC: 0 AN: 32328

South Asian (SAS) AF: 0.0000146 AC: 1 AN: 68426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00000558 AC: 4 AN: 716738

Other (OTH) AF: 0.00 AC: 0 AN: 44022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000117132), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 144456 Hom.: 0 Cov.: 35 AF XY: 0.0000285 AC XY: 2 AN XY: 70116

African (AFR) AF: 0.00 AC: 0 AN: 39706

American (AMR) AF: 0.000141 AC: 2 AN: 14196

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4456

South Asian (SAS) AF: 0.00 AC: 0 AN: 4094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65552

Other (OTH) AF: 0.00 AC: 0 AN: 1954

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000357 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.52
DANN	Benign	0.45
DEOGEN2	Benign	0.0021	T
FATHMM_MKL	Benign	0.00043	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.041	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-1.1
Sift4G	Benign	1.0	T
Vest4		0.041
MVP		0.081
PromoterAI		-0.0094	Neutral
Varity_R		0.14
gMVP		0.028
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760391238; hg19: chr8-11991486;