7-64521484-G-A

Position:

• chr7-64521484-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178558.5(ZNF680):​c.1270C>T​(p.His424Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF680 NM_178558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28

Genes affected

ZNF680 (HGNC:26897): (zinc finger protein 680) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF680	NM_178558.5	c.1270C>T	p.His424Tyr	missense_variant	4/4	ENST00000309683.11	NP_848653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF680	ENST00000309683.11	c.1270C>T	p.His424Tyr	missense_variant	4/4	1	NM_178558.5	ENSP00000309330	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.1270C>T (p.H424Y) alteration is located in exon 4 (coding exon 4) of the ZNF680 gene. This alteration results from a C to T substitution at nucleotide position 1270, causing the histidine (H) at amino acid position 424 to be replaced by a tyrosine (Y). 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	0.91
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0036	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	0.74	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.79		Loss of disorder (P = 0.0582);
MVP		0.90
MPC		0.18
ClinPred		0.99	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.12

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: rs1036774670; hg19: chr7-63981862;