10-56358605-T-C

Variant names:

• chr10-56358605-T-C
• rs1838232055
• NM_007057.4:c.743A>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.743A>G​(p.Glu248Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZWINT NM_007057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0890

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=0.10545534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZWINT	NM_007057.4	c.743A>G	p.Glu248Gly	missense_variant	Exon 7 of 9	ENST00000373944.8	NP_008988.2
ZWINT	NM_032997.3	c.743A>G	p.Glu248Gly	missense_variant	Exon 7 of 8		NP_127490.1
ZWINT	NM_001005413.1	c.602A>G	p.Glu201Gly	missense_variant	Exon 7 of 9		NP_001005413.1
ZWINT	XR_428692.4	n.743A>G		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZWINT	ENST00000373944.8	c.743A>G	p.Glu248Gly	missense_variant	Exon 7 of 9	1	NM_007057.4	ENSP00000363055.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743A>G (p.E248G) alteration is located in exon 7 (coding exon 7) of the ZWINT gene. This alteration results from a A to G substitution at nucleotide position 743, causing the glutamic acid (E) at amino acid position 248 to be replaced by a glycine (G). 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	0.090
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.48	.;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Benign	0.057
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.56	P;P;.;.
Vest4		0.26
MutPred		0.10		Loss of solvent accessibility (P = 0.1362);Loss of solvent accessibility (P = 0.1362);.;.;
MVP		0.18
MPC		0.36
ClinPred		0.70	D
GERP RS		-0.056
Varity_R		0.15
gMVP		0.057

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: rs1838232055; hg19: chr10-58118366;