6-41803837-T-G

Variant names:

• chr6-41803837-T-G
• rs1773061695
• NM_001286554.2:c.1530A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286554.2(USP49):​c.1530A>C​(p.Glu510Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.958
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38442704).

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.1530A>C	p.Glu510Asp	missense	Exon 5 of 8	NP_001273483.1	Q70CQ1-1
	USP49	NM_001384542.1		c.1530A>C	p.Glu510Asp	missense	Exon 5 of 8	NP_001371471.1	Q70CQ1-1
	USP49	NM_018561.5		c.1530A>C	p.Glu510Asp	missense	Exon 5 of 7	NP_061031.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP49	ENST00000682992.1	MANE Select	c.1530A>C	p.Glu510Asp	missense	Exon 5 of 8	ENSP00000507239.1	Q70CQ1-1
	USP49	ENST00000373006.5	TSL:1	c.1530A>C	p.Glu510Asp	missense	Exon 5 of 7	ENSP00000362097.1	Q70CQ1-2
	USP49	ENST00000373010.5	TSL:5	c.1530A>C	p.Glu510Asp	missense	Exon 7 of 10	ENSP00000362101.1	Q5T3E1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000740 Hom.: 0

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.0025
Eigen_PC	Benign	-0.00082
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.96
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.46		Loss of disorder (P = 0.1801)
MVP		0.39
MPC		1.4
ClinPred		0.78	D
GERP RS		0.70
Varity_R		0.12
gMVP		0.40
Mutation Taster		=67/33	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: rs1773061695; hg19: chr6-41771575;