19-21971637-C-G

Position:

• chr19-21971637-C-G

Variant summary

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

The NM_007153.3(ZNF208):​c.3397G>C​(p.Val1133Leu) 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: ZNF208 NM_007153.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.07

Genes affected

ZNF208 (HGNC:12999): (zinc finger protein 208) Zinc finger proteins (ZNFs), such as ZNF208, bind DNA and, through this binding, regulate gene transcription. Most ZNFs contain conserved C2H2 motifs and are classified as Kruppel-type zinc fingers. A conserved protein motif, termed the Kruppel-associated box (KRAB) domain, mediates protein-protein interactions (Eichler et al., 1998 [PubMed 9724325]). See ZNF91 (MIM 603971) for further information on ZNFs.[supplied by OMIM, Aug 2009]

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=0.05422619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF208	NM_007153.3	c.3397G>C	p.Val1133Leu	missense_variant	4/4	ENST00000397126.9	NP_009084.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF208	ENST00000397126.9	c.3397G>C	p.Val1133Leu	missense_variant	4/4	3	NM_007153.3	ENSP00000380315.3
ZNF208	ENST00000599916.5	c.305+3092G>C		intron_variant		1		ENSP00000469254.1
ZNF208	ENST00000601773.5	c.226+15579G>C		intron_variant		2		ENSP00000469887.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 130

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

Dec 21, 2022

The c.3397G>C (p.V1133L) alteration is located in exon 4 (coding exon 4) of the ZNF208 gene. This alteration results from a G to C substitution at nucleotide position 3397, causing the valine (V) at amino acid position 1133 to be replaced by a leucine (L). 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	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.85
DEOGEN2	Benign	0.00066	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	.;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.19	.;N
REVEL	Benign	0.017
Sift	Benign	0.15	.;T
Sift4G	Benign	0.088	T;T
Vest4		0.077
MVP		0.092
MPC		0.0086
ClinPred		0.083	T
GERP RS		0.019
Varity_R		0.036
gMVP		0.0034

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-22154439;