8-134600553-T-A

Variant names:

• chr8-134600553-T-A
• NM_020863.4:c.2358A>T

Variant summary

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

The NM_020863.4(ZFAT):​c.2358A>T​(p.Lys786Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFAT NM_020863.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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-AS1 (HGNC:33992): (ZFAT antisense RNA 1) This gene encodes a small antisense RNA that may be involved in regulating the sense strand locus, zinc finger and AT hook domain containing. This RNA may play a role in B cell function. A single nucleotide polymorphism in the promoter of this gene is associated with an increased risk of autoimmune thyroid disease.[provided by RefSeq, Jan 2010]

ENSG00000278454 (HGNC:):

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=0.35091016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAT	NM_020863.4	c.2358A>T	p.Lys786Asn	missense_variant	Exon 7 of 16	ENST00000377838.8	NP_065914.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAT	ENST00000377838.8	c.2358A>T	p.Lys786Asn	missense_variant	Exon 7 of 16	1	NM_020863.4	ENSP00000367069.3
ZFAT	ENST00000429442.6	c.2322A>T	p.Lys774Asn	missense_variant	Exon 7 of 16	1		ENSP00000394501.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2358A>T (p.K786N) alteration is located in exon 7 (coding exon 7) of the ZFAT gene. This alteration results from a A to T substitution at nucleotide position 2358, causing the lysine (K) at amino acid position 786 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;.;T;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Benign	0.065	T;T;T;T;T;T
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.57
MutPred		0.48		.;.;.;Loss of methylation at K786 (P = 0.0179);.;.;
MVP		0.30
MPC		0.98
ClinPred		0.94	D
GERP RS		1.8
Varity_R		0.19
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-135612796;