chr8-134602310-G-C

Position:

• chr8-134602310-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 403619.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFAT	NM_020863.4	c.1409C>G	p.Ser470Cys	missense_variant	6/16	ENST00000377838.8	NP_065914.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFAT	ENST00000377838.8	c.1409C>G	p.Ser470Cys	missense_variant	6/16	1	NM_020863.4	ENSP00000367069.3
ZFAT	ENST00000429442.6	c.1373C>G	p.Ser458Cys	missense_variant	6/16	1		ENSP00000394501.2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152240 Hom.: 1 Cov.: 33

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

GnomAD3 exomes AF: 0.00205 AC: 512 AN: 249340 Hom.: 3 AF XY: 0.00201 AC XY: 272 AN XY: 135360

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 SAS 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.: 16 Cov.: 31 AF XY: 0.00342 AC XY: 2484 AN XY: 727102

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000659

Gnomad4 NFE exome AF: 0.00425

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74506

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00369 Hom.: 2

Bravo AF: 0.00221

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.00344 AC: 29

ExAC AF: 0.00211 AC: 255

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ZFAT: BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;D;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.
PrimateAI	Uncertain	0.63	T
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	T
GERP RS		6.0
Varity_R		0.36
gMVP		0.60

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: rs112892337; hg19: chr8-135614553;