8-134602310-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020863.4(ZFAT):c.1409C>G(p.Ser470Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,942 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

ZFAT
NM_020863.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 10.0

Publications

14 publications found

Variant links:

COSMIC-nc: COSV106064219

Genes affected

ZFAT (HGNC:19899): (zinc finger and AT-hook domain containing) This gene encodes a protein that likely binds DNA and functions as a transcriptional regulator involved in apoptosis and cell survival. This gene resides in a susceptibility locus for autoimmune thyroid disease (AITD) on chromosome 8q24. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Nov 2009]

ZFAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011439174).

BP6

Variant 8-134602310-G-C is Benign according to our data. Variant chr8-134602310-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403619.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAT	NM_020863.4 link	c.1409C>G	p.Ser470Cys	missense_variant	Exon 6 of 16	ENST00000377838.8	NP_065914.2	Q9P243-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAT	ENST00000377838.8 link	c.1409C>G	p.Ser470Cys	missense_variant	Exon 6 of 16	1	NM_020863.4	ENSP00000367069.3		Q9P243-1
ZFAT	ENST00000429442.6 link	c.1373C>G	p.Ser458Cys	missense_variant	Exon 6 of 16	1		ENSP00000394501.2		F8W7M8

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

320

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00379

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00205

AC:

512

AN:

249340

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000558

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00349

AC:

5104

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

2484

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00310

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00425

AC:

4730

AN:

1112010

Other (OTH)

AF:

0.00373

AC:

225

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

398

796

1193

1591

1989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00210

AC:

320

AN:

152358

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41586

American (AMR)

AF:

0.000784

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00379

AC:

258

AN:

68040

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.00344

AC:

ExAC

AF:

0.00211

AC:

255

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZFAT: BS2 -

not specified

Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with autoimmune thyroid disease - protein involved in t cell homeostasis, however data is limited. Also, frequency is probably too high. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.;D;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;.;D;D;D;D

M_CAP

Benign

0.0082

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

.;.;.;M;.;.

PhyloP100

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

D;D;D;D;D;T

Sift4G

Uncertain

0.023

D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;.;.

Vest4

0.55

MVP

0.60

MPC

0.89

ClinPred

0.038

GERP RS

6.0

Varity_R

0.36

gMVP

0.60

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over