19-53577563-G-A

Position:

• chr19-53577563-G-A

Variant summary

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

The NM_001079906.2(ZNF331):​c.1003G>A​(p.Ala335Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF331 NM_001079906.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0180

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=0.1198425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF331	NM_001079906.2	c.1003G>A	p.Ala335Thr	missense_variant	6/6	ENST00000449416.6	NP_001073375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF331	ENST00000449416.6	c.1003G>A	p.Ala335Thr	missense_variant	6/6	5	NM_001079906.2	ENSP00000393817.1

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 05, 2024

The c.1003G>A (p.A335T) 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 1003, causing the alanine (A) at amino acid position 335 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.18	.;.;.;.;T;.;.;.;.;.;.;.;.
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.86	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	.;N;.;N;N;N;N;.;N;N;.;.;.
REVEL	Benign	0.049
Sift	Benign	0.36	.;T;.;T;T;T;T;.;T;T;.;.;.
Sift4G	Benign	0.43	.;T;.;T;T;T;T;.;T;T;.;.;.
Polyphen		0.43	B;B;B;B;B;B;B;B;B;B;B;B;B
Vest4		0.090, 0.20, 0.17, 0.19, 0.12, 0.12, 0.11
MutPred		0.48		Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);
MVP		0.28
MPC		1.6
ClinPred		0.68	D
GERP RS		3.0
Varity_R		0.064
gMVP		0.086

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: chr19-54080817;