10-56358655-C-G

Position:

• chr10-56358655-C-G

Variant summary

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

The NM_007057.4(ZWINT):​c.693G>C​(p.Glu231Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZWINT NM_007057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

Genes affected

ZWINT (HGNC:13195): (ZW10 interacting kinetochore protein) This gene encodes a protein that is clearly involved in kinetochore function although an exact role is not known. It interacts with ZW10, another kinetochore protein, possibly regulating the association between ZW10 and kinetochores. The encoded protein localizes to prophase kinetochores before ZW10 does and it remains detectable on the kinetochore until late anaphase. It has a uniform distribution in the cytoplasm of interphase cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.106814295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZWINT	NM_007057.4	c.693G>C	p.Glu231Asp	missense_variant	7/9	ENST00000373944.8	NP_008988.2
ZWINT	NM_032997.3	c.693G>C	p.Glu231Asp	missense_variant	7/8		NP_127490.1
ZWINT	NM_001005413.1	c.552G>C	p.Glu184Asp	missense_variant	7/9		NP_001005413.1
ZWINT	XR_428692.4	n.693G>C		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZWINT	ENST00000373944.8	c.693G>C	p.Glu231Asp	missense_variant	7/9	1	NM_007057.4	ENSP00000363055	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.693G>C (p.E231D) alteration is located in exon 7 (coding exon 7) of the ZWINT gene. This alteration results from a G to C substitution at nucleotide position 693, causing the glutamic acid (E) at amino acid position 231 to be replaced by an aspartic acid (D). 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	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	1.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	.;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.34	T;T;T;D
Sift4G	Benign	0.089	T;T;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.18
MutPred		0.29		Loss of glycosylation at P226 (P = 0.2136);Loss of glycosylation at P226 (P = 0.2136);.;.;
MVP		0.33
MPC		0.31
ClinPred		0.43	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.024

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs746108097; hg19: chr10-58118416;