8-12133630-G-A

Variant names:

• chr8-12133630-G-A
• rs141419210
• NM_001256869.2:c.380C>T

Variant summary

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

The NM_001256869.2(USP17L7):​c.380C>T​(p.Thr127Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,229,266 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (8 hom., cov: 35)
  • Exomes 𝑓: 0.00012 (15 hom.)
• Consequence: USP17L7 NM_001256869.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.301
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005510479).
• BP6: Variant 8-12133630-G-A is Benign according to our data. Variant chr8-12133630-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2658419.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 8 gene

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.380C>T	p.Thr127Ile	missense	Exon 1 of 1	NP_001243798.1	P0C7H9
	FAM66D	NR_027425.1		n.608+11580G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP17L7	ENST00000530447.5	TSL:6 MANE Select	c.380C>T	p.Thr127Ile	missense	Exon 1 of 1	ENSP00000485337.2	P0C7H9
	FAM66D	ENST00000434078.3	TSL:5	n.545-12009G>A		intron	N/A
	FAM66D	ENST00000653269.1		n.705+11470G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 178 AN: 144534 Hom.: 8 Cov.: 35

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000774

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000244

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00154

GnomAD2 exomes AF: 0.000259 AC: 60 AN: 231616 AF XY: 0.000150

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.000272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000124 AC: 134 AN: 1084616 Hom.: 15 Cov.: 23 AF XY: 0.000114 AC XY: 63 AN XY: 552522

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

African (AFR) AF: 0.00328 AC: 88 AN: 26850

American (AMR) AF: 0.000470 AC: 20 AN: 42556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23180

East Asian (EAS) AF: 0.00 AC: 0 AN: 32420

South Asian (SAS) AF: 0.00 AC: 0 AN: 69856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3222

European-Non Finnish (NFE) AF: 0.00000760 AC: 6 AN: 789414

Other (OTH) AF: 0.000430 AC: 20 AN: 46560

⚠️ 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: 0.00124 AC: 179 AN: 144650 Hom.: 8 Cov.: 35 AF XY: 0.00134 AC XY: 94 AN XY: 70312

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

African (AFR) AF: 0.00409 AC: 163 AN: 39806

American (AMR) AF: 0.000773 AC: 11 AN: 14232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3352

East Asian (EAS) AF: 0.00 AC: 0 AN: 4430

South Asian (SAS) AF: 0.000244 AC: 1 AN: 4102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65580

Other (OTH) AF: 0.00152 AC: 3 AN: 1972

⚠️ 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: 0.00188 Hom.: 2

ExAC AF: 0.000419 AC: 47

Asia WGS AF: 0.000317 AC: 1 AN: 3164

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	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0055	T
MutationAssessor	Benign	0.13	N
PhyloP100		0.30
Sift4G	Benign	0.24	T
Vest4		0.049
MVP		0.076
PromoterAI		0.054	Neutral
Varity_R		0.070
gMVP		0.020
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: rs141419210; hg19: chr8-11991139;