chr6-41798886-C-T

Variant names:

• chr6-41798886-C-T
• rs575466964
• NM_001286554.2:c.1714G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286554.2(USP49):​c.1714G>A​(p.Val572Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• Publications: 2 publications found

Genes affected

USP49 (HGNC:20078): (ubiquitin specific peptidase 49) Enables cysteine-type endopeptidase activity; histone binding activity; and thiol-dependent deubiquitinase. Involved in histone H2B conserved C-terminal lysine deubiquitination and mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288721 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11039907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286554.2. 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
	USP49	NM_001286554.2	MANE Select	c.1714G>A	p.Val572Ile	missense	Exon 7 of 8	NP_001273483.1	Q70CQ1-1
	USP49	NM_001384542.1		c.1714G>A	p.Val572Ile	missense	Exon 7 of 8	NP_001371471.1	Q70CQ1-1
	USP49	NM_018561.5		c.1714G>A	p.Val572Ile	missense	Exon 7 of 7	NP_061031.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP49	ENST00000682992.1	MANE Select	c.1714G>A	p.Val572Ile	missense	Exon 7 of 8	ENSP00000507239.1	Q70CQ1-1
	USP49	ENST00000373006.5	TSL:1	c.1714G>A	p.Val572Ile	missense	Exon 7 of 7	ENSP00000362097.1	Q70CQ1-2
	USP49	ENST00000373010.5	TSL:5	c.1714G>A	p.Val572Ile	missense	Exon 9 of 10	ENSP00000362101.1	Q5T3E1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151860 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251080 AF XY: 0.0000147

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151978 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.084
Sift	Benign	0.25	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.13
MPC		0.61
ClinPred		0.13	T
GERP RS		5.3
Varity_R		0.025
gMVP		0.11
Mutation Taster		=88/12	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: rs575466964; hg19: chr6-41766624; COSMIC: COSV51898076;