19-53577174-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001079906.2(ZNF331):c.614A>G(p.His205Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.56

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF331	NM_001079906.2	c.614A>G	p.His205Arg	missense_variant	6/6	ENST00000449416.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF331	ENST00000449416.6	c.614A>G	p.His205Arg	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

Aug 22, 2023

The c.614A>G (p.H205R) 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 614, causing the histidine (H) at amino acid position 205 to be replaced by an arginine (R). 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	0.91
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;H;H;H;H;H;H;H;H;H
MutationTaster	Benign	0.60	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Vest4		0.62, 0.57, 0.56, 0.56, 0.62, 0.64, 0.61
MutPred		0.73		Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.85
gMVP		0.78

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: chr19-54080428;