19-8511787-G-C

Variant names:

• chr19-8511787-G-C
• rs375198071
• NM_001146175.2:c.704C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146175.2(ZNF414):​c.704C>G​(p.Pro235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 1,413,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P235L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.53
• Publications: 0 publications found

Genes affected

ZNF414 (HGNC:20630): (zinc finger protein 414) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072194815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.704C>G	p.Pro235Arg	missense_variant	Exon 5 of 8	ENST00000393927.9	NP_001139647.1
ZNF414	NM_032370.3	c.704C>G	p.Pro235Arg	missense_variant	Exon 5 of 6		NP_115746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9	c.704C>G	p.Pro235Arg	missense_variant	Exon 5 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000317 AC: 4 AN: 1261384 Hom.: 0 Cov.: 42 AF XY: 0.00000326 AC XY: 2 AN XY: 612960

African (AFR) AF: 0.00 AC: 0 AN: 25190

American (AMR) AF: 0.00 AC: 0 AN: 15720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17448

East Asian (EAS) AF: 0.00 AC: 0 AN: 30972

South Asian (SAS) AF: 0.00 AC: 0 AN: 58920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000293 AC: 3 AN: 1024534

Other (OTH) AF: 0.0000192 AC: 1 AN: 52060

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.704C>G (p.P235R) alteration is located in exon 5 (coding exon 5) of the ZNF414 gene. This alteration results from a C to G substitution at nucleotide position 704, causing the proline (P) at amino acid position 235 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	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.12
DANN	Benign	0.74
DEOGEN2	Benign	0.0056	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		-3.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.043
Sift	Benign	0.31	T;T
Sift4G	Uncertain	0.011	D;D
Polyphen		0.29	.;B
Vest4		0.10
MutPred		0.24		Loss of glycosylation at P235 (P = 0.0692);Loss of glycosylation at P235 (P = 0.0692);
MVP		0.14
MPC		0.54
ClinPred		0.17	T
GERP RS		-8.9
PromoterAI		-0.019	Neutral
Varity_R		0.069
gMVP		0.28
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs375198071; hg19: chr19-8576671;