7-149239800-C-T

Variant names:

• chr7-149239800-C-T
• rs766270350
• NM_012256.4:c.22C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012256.4(ZNF212):​c.22C>T​(p.Arg8Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,273,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: ZNF212 NM_012256.4 missense, splice_region
• Scores: Splicing: ADA: 0.9660
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

Genes affected

ZNF212 (HGNC:13004): (zinc finger protein 212) This gene belongs to the C2H2-type zinc finger gene family. The zinc finger proteins are involved in gene regulation and development, and are quite conserved throughout evolution. Like this gene product, a third of the zinc finger proteins containing C2H2 fingers also contain the KRAB domain, which has been found to be involved in protein-protein interactions. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012256.4. 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
	ZNF212	NM_012256.4	MANE Select	c.22C>T	p.Arg8Trp	missense splice_region	Exon 1 of 5	NP_036388.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF212	ENST00000335870.7	TSL:1 MANE Select	c.22C>T	p.Arg8Trp	missense splice_region	Exon 1 of 5	ENSP00000338572.2	Q9UDV6
	ZNF212	ENST00000877956.1		c.22C>T	p.Arg8Trp	missense splice_region	Exon 1 of 5	ENSP00000548015.1
	ZNF212	ENST00000462724.1	TSL:5	n.22C>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000418167.1	F2Z3G9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000216 AC: 1 AN: 46350 AF XY: 0.0000416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.91e-7 AC: 1 AN: 1121864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 533258

African (AFR) AF: 0.00 AC: 0 AN: 24132

American (AMR) AF: 0.00 AC: 0 AN: 11126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14668

East Asian (EAS) AF: 0.00 AC: 0 AN: 28394

South Asian (SAS) AF: 0.00 AC: 0 AN: 23082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3854

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 934340

Other (OTH) AF: 0.00 AC: 0 AN: 44846

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

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

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000923 AC: 1

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	Uncertain	0.46
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.035
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.022	D
Polyphen		0.059	B
Vest4		0.26
MutPred		0.25		Loss of solvent accessibility (P = 0.0299)
MVP		0.29
MPC		0.51
ClinPred		0.57	D
GERP RS		3.8
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
gMVP		0.24
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.010		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: rs766270350; hg19: chr7-148936891; COSMIC: COSV60025308;