4-52659116-A-T

Variant names:

• chr4-52659116-A-T
• rs1430933023
• NM_022832.4:c.35T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022832.4(USP46):​c.35T>A​(p.Met12Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: USP46 NM_022832.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009011
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 publications found

Genes affected

USP46 (HGNC:20075): (ubiquitin specific peptidase 46) Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP46 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Jun 2009]

USP46-DT (HGNC:43991): (USP46 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022832.4. 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
	USP46	NM_022832.4	MANE Select	c.35T>A	p.Met12Lys	missense splice_region	Exon 1 of 9	NP_073743.2
	USP46	NM_001286767.2		c.35T>A	p.Met12Lys	missense splice_region	Exon 1 of 9	NP_001273696.1	P62068-4
	USP46	NM_001286768.2		c.-422T>A		splice_region	Exon 1 of 10	NP_001273697.1	P62068-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP46	ENST00000441222.8	TSL:1 MANE Select	c.35T>A	p.Met12Lys	missense splice_region	Exon 1 of 9	ENSP00000407818.2	P62068-1
	USP46	ENST00000903416.1		c.35T>A	p.Met12Lys	missense splice_region	Exon 1 of 9	ENSP00000573475.1
	USP46	ENST00000451218.6	TSL:5	c.35T>A	p.Met12Lys	missense splice_region	Exon 1 of 8	ENSP00000390102.2	H7BZK6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000504 AC: 1 AN: 198570 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414510 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702516

African (AFR) AF: 0.00 AC: 0 AN: 29966

American (AMR) AF: 0.00 AC: 0 AN: 39596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24690

East Asian (EAS) AF: 0.00 AC: 0 AN: 34644

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089682

Other (OTH) AF: 0.00 AC: 0 AN: 58116

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Benign	0.87
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.056	T
Polyphen		0.0	B
Vest4		0.67
MutPred		0.56		Gain of solvent accessibility (P = 0.0137)
MVP		0.49
MPC		1.6
ClinPred		0.50	D
GERP RS		2.8
PromoterAI		-0.15	Neutral
Varity_R		0.84
gMVP		0.73
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.13
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: rs1430933023; hg19: chr4-53525283;