16-3116441-C-A

Variant names:

• chr16-3116441-C-A
• rs759769925
• NM_001042428.2:c.378C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001042428.2(ZNF205):​c.378C>A​(p.Phe126Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF205 NM_001042428.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.171

Genes affected

ZNF205 (HGNC:12996): (zinc finger protein 205) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II; positive regulation of hydrogen peroxide biosynthetic process; and positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF213-AS1 (HGNC:50505): (ZNF213 antisense RNA 1 (head to head))

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF205	NM_001042428.2	c.378C>A	p.Phe126Leu	missense_variant	Exon 5 of 7	ENST00000219091.9	NP_001035893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF205	ENST00000219091.9	c.378C>A	p.Phe126Leu	missense_variant	Exon 5 of 7	5	NM_001042428.2	ENSP00000219091.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.378C>A (p.F126L) alteration is located in exon 5 (coding exon 4) of the ZNF205 gene. This alteration results from a C to A substitution at nucleotide position 378, causing the phenylalanine (F) at amino acid position 126 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.80	.;.;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.0	D;D;.;D
REVEL	Benign	0.14
Sift	Benign	0.030	D;D;.;D
Sift4G	Benign	0.11	T;T;T;D
Polyphen		0.77	P;P;P;.
Vest4		0.51
MutPred		0.88		Loss of phosphorylation at T125 (P = 0.2589);Loss of phosphorylation at T125 (P = 0.2589);Loss of phosphorylation at T125 (P = 0.2589);Loss of phosphorylation at T125 (P = 0.2589);
MVP		0.43
MPC		0.18
ClinPred		0.99	D
GERP RS		-0.88
Varity_R		0.44
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs759769925; hg19: chr16-3166442;