rs374821628

Variant names:

• chr10-56358925-G-A
• rs374821628
• NM_007057.4:c.503C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007057.4(ZWINT):​c.503C>T​(p.Ala168Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ZWINT NM_007057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13594413).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZWINT	NM_007057.4	MANE Select	c.503C>T	p.Ala168Val	missense	Exon 6 of 9	NP_008988.2
	ZWINT	NM_032997.3		c.503C>T	p.Ala168Val	missense	Exon 6 of 8	NP_127490.1	O95229-1
	ZWINT	NM_001005413.1		c.503C>T	p.Ala168Val	missense	Exon 6 of 9	NP_001005413.1	O95229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZWINT	ENST00000373944.8	TSL:1 MANE Select	c.503C>T	p.Ala168Val	missense	Exon 6 of 9	ENSP00000363055.3	O95229-1
	ZWINT	ENST00000318387.7	TSL:1	c.503C>T	p.Ala168Val	missense	Exon 6 of 8	ENSP00000322850.3
	ZWINT	ENST00000920699.1		c.536C>T	p.Ala179Val	missense	Exon 6 of 9	ENSP00000590758.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251210 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 191 AN: 1461856 Hom.: 0 Cov.: 35 AF XY: 0.000131 AC XY: 95 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111998

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74272

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.65
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.19
Sift	Benign	0.038	D
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.15
MVP		0.21
MPC		0.14
ClinPred		0.11	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.021
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs374821628; hg19: chr10-58118686;