1-40540587-A-G

Variant names:

• chr1-40540587-A-G
• rs1646009221
• NM_152373.4:c.17A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_152373.4(ZNF684):​c.17A>G​(p.Glu6Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,443,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZNF684 NM_152373.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002864
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.536

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03174734).
• BP6: Variant 1-40540587-A-G is Benign according to our data. Variant chr1-40540587-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2261525.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF684	NM_152373.4	c.17A>G	p.Glu6Gly	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000372699.8	NP_689586.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF684	ENST00000372699.8	c.17A>G	p.Glu6Gly	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_152373.4	ENSP00000361784.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1443946 Hom.: 0 Cov.: 30 AF XY: 0.00000696 AC XY: 5 AN XY: 718324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 15, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0017	T;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.078	.;T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.96	N;N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Benign	0.075
Sift	Benign	0.14	T;.;T;T
Sift4G	Benign	0.17	T;.;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.053
MutPred		0.41		Loss of stability (P = 0.0494);Loss of stability (P = 0.0494);Loss of stability (P = 0.0494);Loss of stability (P = 0.0494);
MVP		0.014
MPC		0.21
ClinPred		0.11	T
GERP RS		1.6
Varity_R		0.051
gMVP		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.034
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

Publications

LitVar

Other links and lift over

dbSNP: rs1646009221; hg19: chr1-41006259;