16-23068387-G-A

Variant names:

• chr16-23068387-G-A
• rs751973980
• NM_020718.4:c.3718C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020718.4(USP31):​c.3718C>T​(p.Arg1240Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1240H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: USP31 NM_020718.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.901

Genes affected

USP31 (HGNC:20060): (ubiquitin specific peptidase 31) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2015099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP31	NM_020718.4	c.3718C>T	p.Arg1240Cys	missense_variant	Exon 16 of 16	ENST00000219689.12	NP_065769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP31	ENST00000219689.12	c.3718C>T	p.Arg1240Cys	missense_variant	Exon 16 of 16	1	NM_020718.4	ENSP00000219689.7
USP31	ENST00000567975.1	c.1597C>T	p.Arg533Cys	missense_variant	Exon 2 of 2	2		ENSP00000461621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251024 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461628 Hom.: 0 Cov.: 40 AF XY: 0.0000165 AC XY: 12 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3718C>T (p.R1240C) alteration is located in exon 16 (coding exon 16) of the USP31 gene. This alteration results from a C to T substitution at nucleotide position 3718, causing the arginine (R) at amino acid position 1240 to be replaced by a cysteine (C). 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	0.30
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.35		Loss of MoRF binding (P = 0.0386);.;
MVP		0.74
MPC		1.0
ClinPred		0.20	T
GERP RS		0.74
Varity_R		0.22
gMVP		0.36

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: rs751973980; hg19: chr16-23079708;