6-41806253-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286554.2(USP49):​c.731G>A​(p.Arg244His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: USP49 NM_001286554.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28682506).

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.731G>A	p.Arg244His	missense	Exon 4 of 8	NP_001273483.1	Q70CQ1-1
	USP49	NM_001384542.1		c.731G>A	p.Arg244His	missense	Exon 4 of 8	NP_001371471.1	Q70CQ1-1
	USP49	NM_018561.5		c.731G>A	p.Arg244His	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.731G>A	p.Arg244His	missense	Exon 4 of 8	ENSP00000507239.1	Q70CQ1-1
	USP49	ENST00000373006.5	TSL:1	c.731G>A	p.Arg244His	missense	Exon 4 of 7	ENSP00000362097.1	Q70CQ1-2
	USP49	ENST00000373010.5	TSL:5	c.731G>A	p.Arg244His	missense	Exon 6 of 10	ENSP00000362101.1	Q5T3E1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455976 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 724460

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.45		Loss of MoRF binding (P = 0.0126)
MVP		0.42
MPC		1.7
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.10
gMVP		0.48
Mutation Taster		=88/12	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: rs1217488122; hg19: chr6-41773991;