19-53577478-G-C

Variant summary

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

The NM_001079906.2(ZNF331):c.918G>C(p.Lys306Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.891

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF331	NM_001079906.2	c.918G>C	p.Lys306Asn	missense_variant	6/6	ENST00000449416.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF331	ENST00000449416.6	c.918G>C	p.Lys306Asn	missense_variant	6/6	5	NM_001079906.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Feb 17, 2024

The c.918G>C (p.K306N) alteration is located in exon 7 (coding exon 3) of the ZNF331 gene. This alteration results from a G to C substitution at nucleotide position 918, causing the lysine (K) at amino acid position 306 to be replaced by an asparagine (N). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0065	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Vest4		0.23, 0.24, 0.25, 0.25, 0.24, 0.23
MutPred		0.50		Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);Loss of methylation at K306 (P = 0.0026);
MVP		0.72
MPC		1.7
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.70
gMVP		0.23

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: rs548911426; hg19: chr19-54080732;