19-53576769-G-A

Variant summary

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

The NM_001079906.2(ZNF331):c.209G>A(p.Arg70Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

Genes affected

ZNF331 (HGNC:15489): (zinc finger protein 331) This gene encodes a zinc finger protein containing a KRAB (Kruppel-associated box) domain found in transcriptional repressors. This gene may be methylated and silenced in cancer cells. This gene is located within a differentially methylated region (DMR) and shows allele-specific expression in placenta. Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding the same protein. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043913215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF331	NM_001079906.2	c.209G>A	p.Arg70Lys	missense_variant	6/6	ENST00000449416.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF331	ENST00000449416.6	c.209G>A	p.Arg70Lys	missense_variant	6/6	5	NM_001079906.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251114 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135796

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 727146

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: 0.0000315

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.209G>A (p.R70K) alteration is located in exon 7 (coding exon 3) of the ZNF331 gene. This alteration results from a G to A substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.4
Dann	Benign	0.28
DEOGEN2	Benign	0.045	T;T;T;T;T;.;T;T;.;T;T;T;.;T;T;.;T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.044	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.23	N;N;N;N;N;.;N;N;.;N;N;N;.;.;.;.;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
Polyphen		0.0010	B;B;B;B;B;.;B;B;.;B;B;B;.;.;.;.;B;.;B;B
Vest4		0.053, 0.073, 0.074, 0.072, 0.060, 0.057, 0.10
MutPred		0.42		Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);Gain of ubiquitination at R70 (P = 0.0388);
MVP		0.35
MPC		0.61
ClinPred		0.0086	T
GERP RS		0.76
Varity_R		0.026
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs770166196; hg19: chr19-54080023; COSMIC: COSV53474358; COSMIC: COSV53474358;