15-58771946-C-A

Variant names:

• chr15-58771946-C-A
• rs944417978
• NM_001040450.3:c.551C>A

Variant summary

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

The NM_001040450.3(MINDY2):​c.551C>A​(p.Ser184Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000057 in 1,403,724 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: MINDY2 NM_001040450.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

Genes affected

MINDY2 (HGNC:26954): (MINDY lysine 48 deubiquitinase 2) Enables cysteine-type peptidase activity and polyubiquitin modification-dependent protein binding activity. Predicted to be involved in protein K48-linked deubiquitination. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.33430806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINDY2	NM_001040450.3	c.551C>A	p.Ser184Tyr	missense_variant	Exon 1 of 9	ENST00000559228.6	NP_001035540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MINDY2	ENST00000559228.6	c.551C>A	p.Ser184Tyr	missense_variant	Exon 1 of 9	2	NM_001040450.3	ENSP00000452885.1
MINDY2	ENST00000450403.3	c.551C>A	p.Ser184Tyr	missense_variant	Exon 1 of 9	1		ENSP00000393231.2
MINDY2	ENST00000316848.9	n.551C>A		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000326194.5
MINDY2	ENST00000560289.5	n.551C>A		non_coding_transcript_exon_variant	Exon 1 of 9	1		ENSP00000453425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000570 AC: 8 AN: 1403724 Hom.: 0 Cov.: 31 AF XY: 0.00000578 AC XY: 4 AN XY: 692588

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: 0.00000737

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551C>A (p.S184Y) alteration is located in exon 1 (coding exon 1) of the FAM63B gene. This alteration results from a C to A substitution at nucleotide position 551, causing the serine (S) at amino acid position 184 to be replaced by a tyrosine (Y). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.67	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.24		Gain of catalytic residue at S184 (P = 0.0135);Gain of catalytic residue at S184 (P = 0.0135);
MVP		0.75
MPC		0.52
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.79
gMVP		0.53

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: rs944417978; hg19: chr15-59064145; COSMIC: COSV57505439; COSMIC: COSV57505439;