chr8-12133977-G-C

Variant names:

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

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.33C>G​(p.Asp11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,147,188 control chromosomes in the GnomAD database, including 39 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 0.00018 (2 hom., cov: 35)
  • Exomes 𝑓: 0.00040 (37 hom.)
• Consequence: USP17L7 NM_001256869.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010778487).
• BP6: Variant 8-12133977-G-C is Benign according to our data. Variant chr8-12133977-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.33C>G	p.Asp11Glu	missense	Exon 1 of 1	NP_001243798.1	P0C7H9
	FAM66D	NR_027425.1		n.609-11446G>C		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>G	p.Asp11Glu	missense	Exon 1 of 1	ENSP00000485337.2	P0C7H9
	FAM66D	ENST00000434078.3	TSL:5	n.545-11662G>C		intron	N/A
	FAM66D	ENST00000653269.1		n.706-11446G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 27 AN: 144452 Hom.: 2 Cov.: 35

Gnomad AFR AF: 0.0000756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000489

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.000183

Gnomad OTH AF: 0.000512

GnomAD2 exomes AF: 0.000461 AC: 105 AN: 227992 AF XY: 0.000617

Gnomad AFR exome AF: 0.0000731

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000258

Gnomad FIN exome AF: 0.0000552

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000397 AC: 398 AN: 1002626 Hom.: 37 Cov.: 18 AF XY: 0.000507 AC XY: 261 AN XY: 514522

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

African (AFR) AF: 0.000116 AC: 3 AN: 25826

American (AMR) AF: 0.0000939 AC: 4 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: 0.00257 AC: 176 AN: 68410

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46884

Middle Eastern (MID) AF: 0.00484 AC: 15 AN: 3096

European-Non Finnish (NFE) AF: 0.000253 AC: 181 AN: 716712

Other (OTH) AF: 0.000409 AC: 18 AN: 44018

⚠️ 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: 0.000180 AC: 26 AN: 144562 Hom.: 2 Cov.: 35 AF XY: 0.000199 AC XY: 14 AN XY: 70236

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

African (AFR) AF: 0.0000753 AC: 3 AN: 39828

American (AMR) AF: 0.000211 AC: 3 AN: 14212

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4444

South Asian (SAS) AF: 0.000490 AC: 2 AN: 4084

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

Middle Eastern (MID) AF: 0.0185 AC: 5 AN: 270

European-Non Finnish (NFE) AF: 0.000183 AC: 12 AN: 65544

Other (OTH) AF: 0.000507 AC: 1 AN: 1972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000020215), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000158 Hom.: 0

ExAC AF: 0.000402 AC: 45

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	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.3
DANN	Benign	0.34
DEOGEN2	Benign	0.0021	T
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.011	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-1.1
Sift4G	Benign	1.0	T
Vest4		0.041
MVP		0.081
PromoterAI		0.18	Neutral
Varity_R		0.14
gMVP		0.028
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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;