6-41806253-C-A

Variant names:

• chr6-41806253-C-A
• rs1217488122
• NM_001286554.2:c.731G>T

Variant summary

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

The NM_001286554.2(USP49):​c.731G>T​(p.Arg244Leu) 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: 4.45

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=0.31761807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP49	NM_001286554.2	c.731G>T	p.Arg244Leu	missense_variant	Exon 4 of 8	ENST00000682992.1	NP_001273483.1
USP49	NM_001384542.1	c.731G>T	p.Arg244Leu	missense_variant	Exon 4 of 8		NP_001371471.1
USP49	NM_018561.5	c.731G>T	p.Arg244Leu	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.731G>T	p.Arg244Leu	missense_variant	Exon 4 of 8		NM_001286554.2	ENSP00000507239.1
USP49	ENST00000373010.5	c.731G>T	p.Arg244Leu	missense_variant	Exon 6 of 10	5		ENSP00000362101.1
ENSG00000288721	ENST00000684631.1	n.*889G>T		non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1	n.*889G>T		3_prime_UTR_variant	Exon 6 of 10			ENSP00000507261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.731G>T (p.R244L) alteration is located in exon 4 (coding exon 1) of the USP49 gene. This alteration results from a G to T substitution at nucleotide position 731, causing the arginine (R) at amino acid position 244 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		0.47	.;.;P
Vest4		0.51
MutPred		0.48		Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);
MVP		0.19
MPC		1.1
ClinPred		0.88	D
GERP RS		4.1
Varity_R		0.19
gMVP		0.66

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: rs1217488122; hg19: chr6-41773991;