8-134478561-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020863.4(ZFAT):c.3653C>T(p.Ser1218Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,442,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ZFAT NM_020863.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3743549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFAT	NM_020863.4	c.3653C>T	p.Ser1218Leu	missense_variant	16/16	ENST00000377838.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFAT	ENST00000377838.8	c.3653C>T	p.Ser1218Leu	missense_variant	16/16	1	NM_020863.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000138 AC: 3 AN: 216812 Hom.: 0 AF XY: 0.00000852 AC XY: 1 AN XY: 117310

Gnomad AFR exome AF: 0.0000810

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000693 AC: 10 AN: 1442750 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715748

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.00000544

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune thyroid disease, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 14, 2020

The ZFAT c.3653C>T variant is a single nucleotide change from a cytosine to a thymine which is predicted to change the serine at position 1218 in the protein to leucine. The variant has not been described in the literature to date. ZFAT was originally identified as a susceptibility gene for autoimmune thyroid disease (PMID: 15294872). A recent report has identified variants in ZFAT as candidates for intellectual disability (PMID: 28940097). The variant is in dbSNP (rs1428157950) and has been reported in population databases (gnomAD 3/216812, 0 homozygotes) (PM2). The variant has not been reported in the ClinVar or HGMD disease databases. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N;N;N;N;D;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.55
MutPred		0.37		.;.;Gain of catalytic residue at S1218 (P = 8e-04);.;.;.;
MVP		0.52
MPC		0.73
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.17
gMVP		0.36

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: rs1428157950; hg19: chr8-135490804;