chr1-40546589-C-T

Variant names:

• chr1-40546589-C-T
• rs1303613311
• NM_152373.4:c.266C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152373.4(ZNF684):​c.266C>T​(p.Pro89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,414,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF684 NM_152373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.261
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03570199).

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.266C>T	p.Pro89Leu	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.266C>T	p.Pro89Leu	missense	Exon 5 of 5	ENSP00000361784.3	Q5T5D7
	ZNF684	ENST00000921959.1		c.359C>T	p.Pro120Leu	missense	Exon 6 of 6	ENSP00000592018.1
	ZNF684	ENST00000900102.1		c.314C>T	p.Pro105Leu	missense	Exon 5 of 5	ENSP00000570161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1414124 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 699940

African (AFR) AF: 0.0000318 AC: 1 AN: 31408

American (AMR) AF: 0.00 AC: 0 AN: 35266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23610

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.00 AC: 0 AN: 76760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1092192

Other (OTH) AF: 0.0000172 AC: 1 AN: 58278

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.22
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.33	N
PhyloP100		-0.26
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.050
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.077
MutPred		0.30		Loss of loop (P = 0.0804)
MVP		0.014
MPC		0.18
ClinPred		0.12	T
GERP RS		1.1
Varity_R		0.028
gMVP		0.10
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1303613311; hg19: chr1-41012261;