6-41799924-A-G

Position:

• chr6-41799924-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286554.2(USP49):​c.1576T>C​(p.Ser526Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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=0.27669117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2	c.1576T>C	p.Ser526Pro	missense_variant	6/8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.1576T>C	p.Ser526Pro	missense_variant	6/8		NP_001371471.1
USP49	NM_018561.5	c.1576T>C	p.Ser526Pro	missense_variant	6/7		NP_061031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP49	ENST00000682992.1	c.1576T>C	p.Ser526Pro	missense_variant	6/8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.1576T>C	p.Ser526Pro	missense_variant	8/10	5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*1734T>C		non_coding_transcript_exon_variant	8/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*1734T>C		3_prime_UTR_variant	8/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

May 31, 2022

The c.1576T>C (p.S526P) alteration is located in exon 6 (coding exon 3) of the USP49 gene. This alteration results from a T to C substitution at nucleotide position 1576, causing the serine (S) at amino acid position 526 to be replaced by a proline (P). 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	0.40
BayesDel_addAF	Benign	-0.00073	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.22
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.097	T;T;T
Polyphen		0.98	.;.;D
Vest4		0.44
MutPred		0.41		Loss of phosphorylation at S526 (P = 0.0048);Loss of phosphorylation at S526 (P = 0.0048);Loss of phosphorylation at S526 (P = 0.0048);
MVP		0.32
MPC		2.0
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr6-41767662;