chr1-40546588-C-T

Variant names:

• chr1-40546588-C-T
• rs545242034
• NM_152373.4:c.265C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_152373.4(ZNF684):​c.265C>T​(p.Pro89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000447 in 1,566,838 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ZNF684 NM_152373.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.301
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024057806).
• BP6: Variant 1-40546588-C-T is Benign according to our data. Variant chr1-40546588-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2261845.Status of the report is criteria_provided_single_submitter, 1 stars.

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.265C>T	p.Pro89Ser	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.265C>T	p.Pro89Ser	missense	Exon 5 of 5	ENSP00000361784.3	Q5T5D7
	ZNF684	ENST00000921959.1		c.358C>T	p.Pro120Ser	missense	Exon 6 of 6	ENSP00000592018.1
	ZNF684	ENST00000900102.1		c.313C>T	p.Pro105Ser	missense	Exon 5 of 5	ENSP00000570161.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1414752 Hom.: 0 Cov.: 30 AF XY: 0.00000571 AC XY: 4 AN XY: 700354

African (AFR) AF: 0.00 AC: 0 AN: 31446

American (AMR) AF: 0.00 AC: 0 AN: 35298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.00 AC: 0 AN: 76852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1092550

Other (OTH) AF: 0.00 AC: 0 AN: 58344

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.54
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.97	N
PhyloP100		-0.30
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.048
Sift	Benign	0.75	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.033
MutPred		0.24		Gain of glycosylation at P89 (P = 0.0182)
MVP		0.014
MPC		0.18
ClinPred		0.042	T
GERP RS		0.78
Varity_R		0.027
gMVP		0.066
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs545242034; hg19: chr1-41012260;