10-124972080-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017580.3(ZRANB1):c.1118A>G(p.Tyr373Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZRANB1 NM_017580.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

ZRANB1 (HGNC:18224): (zinc finger RANBP2-type containing 1) Enables K63-linked polyubiquitin modification-dependent protein binding activity and thiol-dependent deubiquitinase. Involved in several processes, including positive regulation of Wnt signaling pathway; protein deubiquitination; and regulation of cell morphogenesis. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ZRANB1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZRANB1	NM_017580.3	c.1118A>G	p.Tyr373Cys	missense_variant	3/9	ENST00000359653.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZRANB1	ENST00000359653.4	c.1118A>G	p.Tyr373Cys	missense_variant	3/9	1	NM_017580.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250982 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727074

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.1118A>G (p.Y373C) alteration is located in exon 3 (coding exon 3) of the ZRANB1 gene. This alteration results from a A to G substitution at nucleotide position 1118, causing the tyrosine (Y) at amino acid position 373 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	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.34	B
Vest4		0.94
MutPred		0.42		Gain of sheet (P = 0.1451);
MVP		0.46
MPC		1.0
ClinPred		0.76	D
GERP RS		4.3
Varity_R		0.39
gMVP		0.85

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: rs778022551; hg19: chr10-126660649; COSMIC: COSV62841968;