rs756693470

Variant names:

• chr7-112330161-G-A
• rs756693470
• NM_021994.3:c.746G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-112330161-G-A
• chr7-112330161-G-C
• chr7-112330161-G-T

Variant summary

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

The NM_021994.3(ZNF277):​c.746G>A​(p.Arg249His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,460,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ZNF277 NM_021994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.62
• Publications: 0 publications found

Genes affected

ZNF277 (HGNC:13070): (zinc finger protein 277) Predicted to enable RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and metal ion binding activity. Predicted to act upstream of or within cellular response to hydrogen peroxide and regulation of cellular senescence. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF277-AS1 (HGNC:55828): (ZNF277 antisense RNA 1)

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_021994.3. 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
	ZNF277	NM_021994.3	MANE Select	c.746G>A	p.Arg249His	missense	Exon 7 of 12	NP_068834.2	Q9NRM2
	ZNF277-AS1	NR_186626.1		n.147-1763C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF277	ENST00000361822.8	TSL:1 MANE Select	c.746G>A	p.Arg249His	missense	Exon 7 of 12	ENSP00000354501.3	Q9NRM2
	ZNF277	ENST00000450657.1	TSL:1	c.746G>A	p.Arg249His	missense	Exon 7 of 7	ENSP00000402292.1	G5E9M4
	ZNF277	ENST00000361946.8	TSL:1	n.*589G>A		non_coding_transcript_exon	Exon 7 of 12	ENSP00000355043.4	E7EW13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250544 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460806 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726780

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39604

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111598

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.093	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.36		Loss of MoRF binding (P = 0.0167)
MVP		0.52
MPC		0.59
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.31
gMVP		0.53
Mutation Taster		=44/56	disease causing

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

dbSNP: rs756693470; hg19: chr7-111970216;