7-64521483-T-A

Variant names:

• chr7-64521483-T-A
• rs746475615
• NM_178558.5:c.1271A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178558.5(ZNF680):​c.1271A>T​(p.His424Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H424P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF680 NM_178558.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.72
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178558.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF680	NM_178558.5	MANE Select	c.1271A>T	p.His424Leu	missense	Exon 4 of 4	NP_848653.2	Q8NEM1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF680	ENST00000309683.11	TSL:1 MANE Select	c.1271A>T	p.His424Leu	missense	Exon 4 of 4	ENSP00000309330.6	Q8NEM1-1
	ZNF680	ENST00000920524.1		c.1313A>T	p.His438Leu	missense	Exon 4 of 4	ENSP00000590583.1
	ZNF680	ENST00000920523.1		c.1175A>T	p.His392Leu	missense	Exon 3 of 3	ENSP00000590582.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461434 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0043	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.81		Loss of methylation at K425 (P = 0.0666)
MVP		0.92
MPC		0.18
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.15
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs746475615; hg19: chr7-63981861;