1-40546964-C-A

Variant names:

• chr1-40546964-C-A
• rs1402854520
• NM_152373.4:c.641C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152373.4(ZNF684):​c.641C>A​(p.Pro214His) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P214R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZNF684 NM_152373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72
• Publications: 0 publications found

Genes affected

ZNF684 (HGNC:28418): (zinc finger protein 684) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to act upstream of or within innate immune response and negative regulation of single stranded viral RNA replication via double stranded DNA intermediate. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152373.4. 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
	ZNF684	NM_152373.4	MANE Select	c.641C>A	p.Pro214His	missense	Exon 5 of 5	NP_689586.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF684	ENST00000372699.8	TSL:1 MANE Select	c.641C>A	p.Pro214His	missense	Exon 5 of 5	ENSP00000361784.3	Q5T5D7
	ZNF684	ENST00000921959.1		c.734C>A	p.Pro245His	missense	Exon 6 of 6	ENSP00000592018.1
	ZNF684	ENST00000900102.1		c.689C>A	p.Pro230His	missense	Exon 5 of 5	ENSP00000570161.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0047	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.66		Gain of disorder (P = 0.1594)
MVP		0.072
MPC		0.26
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.77
gMVP		0.054
Mutation Taster		=95/5	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: rs1402854520; hg19: chr1-41012636;