6-41803837-T-G

Position:

• chr6-41803837-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 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

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 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2	c.1530A>C	p.Glu510Asp	missense_variant	5/8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.1530A>C	p.Glu510Asp	missense_variant	5/8		NP_001371471.1
USP49	NM_018561.5	c.1530A>C	p.Glu510Asp	missense_variant	5/7		NP_061031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP49	ENST00000682992.1	c.1530A>C	p.Glu510Asp	missense_variant	5/8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.1530A>C	p.Glu510Asp	missense_variant	7/10	5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*1688A>C		non_coding_transcript_exon_variant	7/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*1688A>C		3_prime_UTR_variant	7/10			ENSP00000507261.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000740 Hom.: 0

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

Oct 25, 2022

The c.1530A>C (p.E510D) alteration is located in exon 5 (coding exon 2) of the USP49 gene. This alteration results from a A to C substitution at nucleotide position 1530, causing the glutamic acid (E) at amino acid position 510 to be replaced by an aspartic acid (D). 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	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;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.61
MutPred		0.46		Loss of disorder (P = 0.1801);Loss of disorder (P = 0.1801);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1773061695; hg19: chr6-41771575;