NM_001256869.2:c.145T>G

Variant names:

• chr8-12133865-A-C
• rs748545592
• NM_001256869.2:c.145T>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.145T>G​(p.Phe49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,377,324 control chromosomes in the GnomAD database, including 26 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 0.0014 (2 hom., cov: 35)
  • Exomes 𝑓: 0.00015 (26 hom.)
  • Failed GnomAD Quality Control
• Consequence: USP17L7 NM_001256869.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.08
• 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=0.0062601864).
• BP6: Variant 8-12133865-A-C is Benign according to our data. Variant chr8-12133865-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 26 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.145T>G	p.Phe49Val	missense	Exon 1 of 1	NP_001243798.1	P0C7H9
	FAM66D	NR_027425.1		n.609-11558A>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.145T>G	p.Phe49Val	missense	Exon 1 of 1	ENSP00000485337.2	P0C7H9
	FAM66D	ENST00000434078.3	TSL:5	n.545-11774A>C		intron	N/A
	FAM66D	ENST00000653269.1		n.706-11558A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 204 AN: 143668 Hom.: 2 Cov.: 35

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000777

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000681

Gnomad SAS AF: 0.000248

Gnomad FIN AF: 0.0000994

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000458

Gnomad OTH AF: 0.00206

GnomAD2 exomes AF: 0.000462 AC: 107 AN: 231408 AF XY: 0.000348

Gnomad AFR exome AF: 0.00509

Gnomad AMR exome AF: 0.0000906

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.000449

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.0000473

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.000152 AC: 209 AN: 1377324 Hom.: 26 Cov.: 32 AF XY: 0.000140 AC XY: 96 AN XY: 685490

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

African (AFR) AF: 0.00348 AC: 110 AN: 31600

American (AMR) AF: 0.000232 AC: 10 AN: 43068

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25060

East Asian (EAS) AF: 0.000350 AC: 12 AN: 34256

South Asian (SAS) AF: 0.000364 AC: 28 AN: 76862

European-Finnish (FIN) AF: 0.000138 AC: 7 AN: 50614

Middle Eastern (MID) AF: 0.000260 AC: 1 AN: 3842

European-Non Finnish (NFE) AF: 0.0000246 AC: 26 AN: 1055378

Other (OTH) AF: 0.000247 AC: 14 AN: 56644

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00141 AC: 203 AN: 143776 Hom.: 2 Cov.: 35 AF XY: 0.00106 AC XY: 74 AN XY: 69874

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

African (AFR) AF: 0.00460 AC: 180 AN: 39146

American (AMR) AF: 0.000776 AC: 11 AN: 14178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.000683 AC: 3 AN: 4392

South Asian (SAS) AF: 0.000248 AC: 1 AN: 4030

European-Finnish (FIN) AF: 0.0000994 AC: 1 AN: 10062

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

European-Non Finnish (NFE) AF: 0.0000458 AC: 3 AN: 65540

Other (OTH) AF: 0.00204 AC: 4 AN: 1962

⚠️ 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: 0.000488 Hom.: 0

ExAC AF: 0.00110 AC: 123

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	0.052
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.1
DANN	Benign	0.19
DEOGEN2	Benign	0.0023	T
FATHMM_MKL	Benign	0.000090	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0063	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-1.1
Sift4G	Benign	0.73	T
Vest4		0.023
MVP		0.17
PromoterAI		-0.027	Neutral
Varity_R		0.069
gMVP		0.040
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: rs748545592; hg19: chr8-11991374; COSMIC: COSV105883998; COSMIC: COSV105883998;