18-35369598-C-T

Variant names:

• chr18-35369598-C-T
• NM_001322286.2:c.625G>A

Variant summary

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

The NM_001322286.2(ZNF396):​c.625G>A​(p.Glu209Lys) 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. 13/21 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: ZNF396 NM_001322286.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0790

Genes affected

ZNF396 (HGNC:18824): (zinc finger protein 396) Enables protein heterodimerization activity; protein homodimerization activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription, DNA-templated. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.19342986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF396	NM_001322286.2	c.625G>A	p.Glu209Lys	missense_variant	Exon 4 of 4	ENST00000589332.7	NP_001309215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF396	ENST00000589332.7	c.625G>A	p.Glu209Lys	missense_variant	Exon 4 of 4	1	NM_001322286.2	ENSP00000466500.1
ZNF396	ENST00000306346.5	c.625G>A	p.Glu209Lys	missense_variant	Exon 4 of 5	1		ENSP00000302310.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625G>A (p.E209K) alteration is located in exon 4 (coding exon 3) of the ZNF396 gene. This alteration results from a G to A substitution at nucleotide position 625, causing the glutamic acid (E) at amino acid position 209 to be replaced by a lysine (K). 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	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.066
Sift	Benign	0.17	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.93	P;.
Vest4		0.15
MutPred		0.49		Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);
MVP		0.23
MPC		0.47
ClinPred		0.73	D
GERP RS		4.0
Varity_R		0.14
gMVP		0.11

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: chr18-32949562;