1-40540707-C-T

Variant names:

• chr1-40540707-C-T
• NM_152373.4:c.137C>T

Variant summary

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

The NM_152373.4(ZNF684):​c.137C>T​(p.Ser46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF684 NM_152373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• 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.137C>T	p.Ser46Leu	missense	Exon 3 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.137C>T	p.Ser46Leu	missense	Exon 3 of 5	ENSP00000361784.3	Q5T5D7
	ZNF684	ENST00000921959.1		c.230C>T	p.Ser77Leu	missense	Exon 4 of 6	ENSP00000592018.1
	ZNF684	ENST00000900102.1		c.185C>T	p.Ser62Leu	missense	Exon 3 of 5	ENSP00000570161.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.50
MutPred		0.76		Gain of helix (P = 0.0854)
MVP		0.048
MPC		0.16
ClinPred		0.86	D
GERP RS		3.8
Varity_R		0.46
gMVP		0.24
Mutation Taster		=90/10	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

hg19: chr1-41006379; COSMIC: COSV65519157; COSMIC: COSV65519157;