chr1-40546600-C-T

Variant names:

• chr1-40546600-C-T
• rs199950841
• NM_152373.4:c.277C>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.277C>T​(p.Arg93Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,578,340 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ZNF684 NM_152373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.788
• Publications: 2 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=0.03131509).

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.277C>T	p.Arg93Trp	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.277C>T	p.Arg93Trp	missense	Exon 5 of 5	ENSP00000361784.3	Q5T5D7
	ZNF684	ENST00000921959.1		c.370C>T	p.Arg124Trp	missense	Exon 6 of 6	ENSP00000592018.1
	ZNF684	ENST00000900102.1		c.325C>T	p.Arg109Trp	missense	Exon 5 of 5	ENSP00000570161.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000530 AC: 12 AN: 226406 AF XY: 0.0000572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000710

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000471

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 85 AN: 1426140 Hom.: 0 Cov.: 30 AF XY: 0.0000580 AC XY: 41 AN XY: 706722

African (AFR) AF: 0.00 AC: 0 AN: 31866

American (AMR) AF: 0.0000534 AC: 2 AN: 37460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24356

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39222

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.0000711 AC: 78 AN: 1097036

Other (OTH) AF: 0.0000170 AC: 1 AN: 58854

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74410

African (AFR) AF: 0.0000241 AC: 1 AN: 41520

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.38
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.79
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.029
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.020	D
Polyphen		0.0	B
Vest4		0.089
MVP		0.014
MPC		0.19
ClinPred		0.047	T
GERP RS		1.0
Varity_R		0.061
gMVP		0.24
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs199950841; hg19: chr1-41012272; COSMIC: COSV65519715; COSMIC: COSV65519715;