6-41805863-G-A

Variant names:

• chr6-41805863-G-A
• NM_001286554.2:c.1121C>T

Variant summary

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

The NM_001286554.2(USP49):​c.1121C>T​(p.Ala374Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP49	NM_001286554.2	c.1121C>T	p.Ala374Val	missense_variant	Exon 4 of 8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.1121C>T	p.Ala374Val	missense_variant	Exon 4 of 8		NP_001371471.1
USP49	NM_018561.5	c.1121C>T	p.Ala374Val	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.1121C>T	p.Ala374Val	missense_variant	Exon 4 of 8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.1121C>T	p.Ala374Val	missense_variant	Exon 6 of 10	5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*1279C>T		non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*1279C>T		3_prime_UTR_variant	Exon 6 of 10			ENSP00000507261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461714 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1121C>T (p.A374V) alteration is located in exon 4 (coding exon 1) of the USP49 gene. This alteration results from a C to T substitution at nucleotide position 1121, causing the alanine (A) at amino acid position 374 to be replaced by a valine (V). 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	0.27
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.087	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.048	D;T;T
Polyphen		1.0	.;.;D
Vest4		0.45
MutPred		0.54		Loss of ubiquitination at K372 (P = 0.0962);Loss of ubiquitination at K372 (P = 0.0962);Loss of ubiquitination at K372 (P = 0.0962);
MVP		0.47
MPC		1.6
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41773601;