2-218495761-C-T

Variant names:

• chr2-218495761-C-T
• rs766752595
• NM_020935.3:c.1471G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_020935.3(USP37):​c.1471G>A​(p.Ala491Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USP37 NM_020935.3 missense, splice_region
• Scores: Splicing: ADA: 0.9505
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

Genes affected

USP37 (HGNC:20063): (ubiquitin specific peptidase 37) Enables cysteine-type endopeptidase activity; protein kinase binding activity; and thiol-dependent deubiquitinase. Involved in G1/S transition of mitotic cell cycle; protein deubiquitination; and regulation of DNA replication. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10399139).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP37	NM_020935.3	c.1471G>A	p.Ala491Thr	missense_variant, splice_region_variant	Exon 14 of 26	ENST00000258399.8	NP_065986.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP37	ENST00000258399.8	c.1471G>A	p.Ala491Thr	missense_variant, splice_region_variant	Exon 14 of 26	1	NM_020935.3	ENSP00000258399.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245310 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455436 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723898

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: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0075	T;T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N;N;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.048
Sift	Benign	0.077	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0040	B;B;B;B
Vest4		0.15
MutPred		0.32		Gain of ubiquitination at K490 (P = 0.1489);Gain of ubiquitination at K490 (P = 0.1489);.;Gain of ubiquitination at K490 (P = 0.1489);
MVP		0.12
MPC		0.30
ClinPred		0.23	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.61
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: rs766752595; hg19: chr2-219360484;