19-53577075-A-G

Variant summary

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

The NM_001079906.2(ZNF331):c.515A>G(p.Asn172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.717

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=0.035930097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF331	NM_001079906.2	c.515A>G	p.Asn172Ser	missense_variant	6/6	ENST00000449416.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF331	ENST00000449416.6	c.515A>G	p.Asn172Ser	missense_variant	6/6	5	NM_001079906.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

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

Sep 22, 2023

The c.515A>G (p.N172S) alteration is located in exon 7 (coding exon 3) of the ZNF331 gene. This alteration results from a A to G substitution at nucleotide position 515, causing the asparagine (N) at amino acid position 172 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	11
Dann	Benign	0.23
DEOGEN2	Benign	0.034	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.036	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.7	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	0.45	T
Polyphen		0.030	B;B;B;B;B;B;B;B;B;B;.;B;B;B
Vest4		0.040, 0.083, 0.067, 0.078, 0.043, 0.046, 0.042
MutPred		0.41		Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);
MVP		0.29
MPC		0.50
ClinPred		0.057	T
GERP RS		2.5
Varity_R		0.037
gMVP		0.023

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54080329;