19-53576856-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079906.2(ZNF331):c.296A>T(p.Tyr99Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.352

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12172809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF331	NM_001079906.2	c.296A>T	p.Tyr99Phe	missense_variant	6/6	ENST00000449416.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF331	ENST00000449416.6	c.296A>T	p.Tyr99Phe	missense_variant	6/6	5	NM_001079906.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 15, 2021

The c.296A>T (p.Y99F) alteration is located in exon 7 (coding exon 3) of the ZNF331 gene. This alteration results from a A to T substitution at nucleotide position 296, causing the tyrosine (Y) at amino acid position 99 to be replaced by a phenylalanine (F). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.4
Dann	Benign	0.65
DEOGEN2	Benign	0.091	T;T;T;T;T;.;T;T;T;T;T;.;T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.067	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;L;L;L;L;.;L;L;L;L;L;.;.;.;L;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
Polyphen		0.072	B;B;B;B;B;.;B;B;B;B;B;.;.;.;B;B;B
Vest4		0.13, 0.13, 0.12, 0.13, 0.12, 0.14, 0.12
MutPred		0.34		Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);Loss of phosphorylation at Y99 (P = 0.0457);
MVP		0.23
MPC		0.56
ClinPred		0.021	T
GERP RS		-0.26
Varity_R		0.052
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1387980508; hg19: chr19-54080110;