chr6-41806027-A-C

Variant names:

• chr6-41806027-A-C
• rs778956931
• NM_001286554.2:c.957T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286554.2(USP49):​c.957T>G​(p.Asn319Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0760
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027285308).

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.957T>G	p.Asn319Lys	missense	Exon 4 of 8	NP_001273483.1	Q70CQ1-1
	USP49	NM_001384542.1		c.957T>G	p.Asn319Lys	missense	Exon 4 of 8	NP_001371471.1	Q70CQ1-1
	USP49	NM_018561.5		c.957T>G	p.Asn319Lys	missense	Exon 4 of 7	NP_061031.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP49	ENST00000682992.1	MANE Select	c.957T>G	p.Asn319Lys	missense	Exon 4 of 8	ENSP00000507239.1	Q70CQ1-1
	USP49	ENST00000373006.5	TSL:1	c.957T>G	p.Asn319Lys	missense	Exon 4 of 7	ENSP00000362097.1	Q70CQ1-2
	USP49	ENST00000373010.5	TSL:5	c.957T>G	p.Asn319Lys	missense	Exon 6 of 10	ENSP00000362101.1	Q5T3E1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250598 AF XY: 0.00

Gnomad AFR exome AF: 0.0000632

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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	0.095
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.43
DANN	Benign	0.29
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.65	N
PhyloP100		0.076
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.40		Gain of ubiquitination at N319 (P = 7e-04)
MVP		0.082
MPC		0.88
ClinPred		0.031	T
GERP RS		0.95
Varity_R		0.033
gMVP		0.13
Mutation Taster		=83/17	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: rs778956931; hg19: chr6-41773765;