rs369560206

Variant names:

• chr19-8511958-C-A
• NM_001146175.2:c.533G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-8511958-C-A
• chr19-8511958-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001146175.2(ZNF414):​c.533G>T​(p.Cys178Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000079 in 1,265,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C178Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.533G>T	p.Cys178Phe	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000393927.9	NP_001139647.1
ZNF414	NM_032370.3	c.533G>T	p.Cys178Phe	missense_variant, splice_region_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.533G>T	p.Cys178Phe	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1265578 Hom.: 0 Cov.: 41 AF XY: 0.00000163 AC XY: 1 AN XY: 614630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000184

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.4	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.85		Gain of MoRF binding (P = 0.0778);Gain of MoRF binding (P = 0.0778);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.83

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: chr19-8576842;