NM_001146175.2:c.695C>T

Variant names:

• chr19-8511796-G-A
• rs748778876
• NM_001146175.2:c.695C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001146175.2(ZNF414):​c.695C>T​(p.Pro232Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,409,984 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005714059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.695C>T	p.Pro232Leu	missense_variant	Exon 5 of 8	ENST00000393927.9	NP_001139647.1
ZNF414	NM_032370.3	c.695C>T	p.Pro232Leu	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.695C>T	p.Pro232Leu	missense_variant	Exon 5 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152170 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000668 AC: 31 AN: 46382 AF XY: 0.000653

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000231 AC: 290 AN: 1257706 Hom.: 0 Cov.: 42 AF XY: 0.000211 AC XY: 129 AN XY: 610816

African (AFR) AF: 0.00 AC: 0 AN: 25090

American (AMR) AF: 0.00258 AC: 39 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30830

South Asian (SAS) AF: 0.00 AC: 0 AN: 58206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31724

Middle Eastern (MID) AF: 0.000462 AC: 2 AN: 4330

European-Non Finnish (NFE) AF: 0.000227 AC: 232 AN: 1023098

Other (OTH) AF: 0.000327 AC: 17 AN: 51948

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152278 Hom.: 0 Cov.: 34 AF XY: 0.000470 AC XY: 35 AN XY: 74448

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.00399 AC: 61 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67986

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000820

ExAC AF: 0.000286 AC: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.695C>T (p.P232L) alteration is located in exon 5 (coding exon 5) of the ZNF414 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the proline (P) at amino acid position 232 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	0.087
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.0054	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N;N
PhyloP100		1.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.050
Sift	Benign	0.25	T;T
Sift4G	Benign	0.078	T;T
Polyphen		0.0	.;B
Vest4		0.096
MutPred		0.33		Loss of glycosylation at P232 (P = 0.0486);Loss of glycosylation at P232 (P = 0.0486);
MVP		0.15
MPC		0.24
ClinPred		0.021	T
GERP RS		0.71
PromoterAI		0.012	Neutral
Varity_R		0.030
gMVP		0.42
Mutation Taster		=96/4	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

Publications

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Other links and lift over

dbSNP: rs748778876; hg19: chr19-8576680;