6-41806027-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

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

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 Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP49	NM_001286554.2	c.957T>G	p.Asn319Lys	missense_variant	Exon 4 of 8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.957T>G	p.Asn319Lys	missense_variant	Exon 4 of 8		NP_001371471.1
USP49	NM_018561.5	c.957T>G	p.Asn319Lys	missense_variant	Exon 4 of 7		NP_061031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP49	ENST00000682992.1	c.957T>G	p.Asn319Lys	missense_variant	Exon 4 of 8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.957T>G	p.Asn319Lys	missense_variant	Exon 6 of 10	5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*1115T>G		non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*1115T>G		3_prime_UTR_variant	Exon 6 of 10			ENSP00000507261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250598 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135762

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 SAS 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.957T>G (p.N319K) alteration is located in exon 4 (coding exon 1) of the USP49 gene. This alteration results from a T to G substitution at nucleotide position 957, causing the asparagine (N) at amino acid position 319 to be replaced by a lysine (K). 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	0.095
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;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.65	N;.;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.024
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0040	.;.;B
Vest4		0.11
MutPred		0.40		Gain of ubiquitination at N319 (P = 7e-04);Gain of ubiquitination at N319 (P = 7e-04);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

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: rs778956931; hg19: chr6-41773765;