chr7-112330161-G-T

Variant names:

• chr7-112330161-G-T
• rs756693470
• NM_021994.3:c.746G>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>T​(p.Arg249Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,808 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R249H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF277 NM_021994.3 missense
• Clinical Significance: Not reported in ClinVar
• 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>T	p.Arg249Leu	missense	Exon 7 of 12	NP_068834.2	Q9NRM2
	ZNF277-AS1	NR_186626.1		n.147-1763C>A		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>T	p.Arg249Leu	missense	Exon 7 of 12	ENSP00000354501.3	Q9NRM2
	ZNF277	ENST00000450657.1	TSL:1	c.746G>T	p.Arg249Leu	missense	Exon 7 of 7	ENSP00000402292.1	G5E9M4
	ZNF277	ENST00000361946.8	TSL:1	n.*589G>T		non_coding_transcript_exon	Exon 7 of 12	ENSP00000355043.4	E7EW13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460808 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 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: 9.00e-7 AC: 1 AN: 1111600

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.38		Loss of solvent accessibility (P = 0.0098)
MVP		0.65
MPC		0.52
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.51
gMVP		0.63
Mutation Taster		=24/76	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;