8-134478659-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000429442.6(ZFAT):c.3409G>A(p.Val1137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,583,022 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: ZFAT ENST00000429442.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034586787).
• BP6: Variant 8-134478659-C-T is Benign according to our data. Variant chr8-134478659-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFAT	NM_020863.4	c.3555G>A	p.Ala1185=	synonymous_variant	16/16	ENST00000377838.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFAT	ENST00000377838.8	c.3555G>A	p.Ala1185=	synonymous_variant	16/16	1	NM_020863.4	P4

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000472 AC: 94 AN: 199060 Hom.: 1 AF XY: 0.000383 AC XY: 41 AN XY: 107080

Gnomad AFR exome AF: 0.00590

Gnomad AMR exome AF: 0.000372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000586

GnomAD4 exome AF: 0.000361 AC: 517 AN: 1430704 Hom.: 4 Cov.: 32 AF XY: 0.000370 AC XY: 262 AN XY: 708592

Gnomad4 AFR exome AF: 0.00599

Gnomad4 AMR exome AF: 0.000345

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74492

Gnomad4 AFR AF: 0.00594

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00176

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00459 AC: 19

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000475 AC: 57

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	ZFAT: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.95
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.050
Sift	Uncertain	0.024	D
Sift4G	Benign	0.21	T
Vest4		0.014
MVP		0.061
ClinPred		0.0091	T
GERP RS		-1.8

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: rs188324571; hg19: chr8-135490902; COSMIC: COSV100914640;