chr6-41798842-G-T

Position:

• chr6-41798842-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286554.2(USP49):​c.1758C>A​(p.Asp586Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08577433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2	c.1758C>A	p.Asp586Glu	missense_variant	7/8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.1758C>A	p.Asp586Glu	missense_variant	7/8		NP_001371471.1
USP49	NM_018561.5	c.1758C>A	p.Asp586Glu	missense_variant	7/7		NP_061031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP49	ENST00000682992.1	c.1758C>A	p.Asp586Glu	missense_variant	7/8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.1725+33C>A		intron_variant		5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*1916C>A		non_coding_transcript_exon_variant	9/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*1916C>A		3_prime_UTR_variant	9/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The c.1758C>A (p.D586E) alteration is located in exon 7 (coding exon 4) of the USP49 gene. This alteration results from a C to A substitution at nucleotide position 1758, causing the aspartic acid (D) at amino acid position 586 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.0095	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.29	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.14
Sift	Benign	0.96	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	.;B
Vest4		0.19
MutPred		0.41		Gain of catalytic residue at D586 (P = 0.2199);Gain of catalytic residue at D586 (P = 0.2199);
MVP		0.32
MPC		0.82
ClinPred		0.42	T
GERP RS		6.2
Varity_R		0.18
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41766580;