19-8510886-G-A

Variant names:

• chr19-8510886-G-A
• rs576116806
• NM_001146175.2:c.1064C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001146175.2(ZNF414):​c.1064C>T​(p.Pro355Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,124,106 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810

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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041778684).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.1064C>T	p.Pro355Leu	missense_variant	Exon 7 of 8	ENST00000393927.9	NP_001139647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9	c.1064C>T	p.Pro355Leu	missense_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 255 AN: 145660 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000407

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00523

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.000492

GnomAD2 exomes AF: 0.00496 AC: 18 AN: 3632 AF XY: 0.00485

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00729

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00120 AC: 1175 AN: 978334 Hom.: 6 Cov.: 32 AF XY: 0.00125 AC XY: 577 AN XY: 460962

African (AFR) AF: 0.000154 AC: 3 AN: 19480

American (AMR) AF: 0.00108 AC: 6 AN: 5530

Ashkenazi Jewish (ASJ) AF: 0.0000969 AC: 1 AN: 10324

East Asian (EAS) AF: 0.00 AC: 0 AN: 18500

South Asian (SAS) AF: 0.00169 AC: 32 AN: 18928

European-Finnish (FIN) AF: 0.00653 AC: 141 AN: 21578

Middle Eastern (MID) AF: 0.00250 AC: 6 AN: 2402

European-Non Finnish (NFE) AF: 0.00112 AC: 950 AN: 844744

Other (OTH) AF: 0.000977 AC: 36 AN: 36848

GnomAD4 genome AF: 0.00174 AC: 254 AN: 145772 Hom.: 2 Cov.: 32 AF XY: 0.00186 AC XY: 132 AN XY: 70920

African (AFR) AF: 0.000147 AC: 6 AN: 40798

American (AMR) AF: 0.000407 AC: 6 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4804

European-Finnish (FIN) AF: 0.00523 AC: 44 AN: 8412

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00290 AC: 189 AN: 65236

Other (OTH) AF: 0.000487 AC: 1 AN: 2054

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000963

ExAC AF: 0.000406 AC: 2

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.1064C>T (p.P355L) alteration is located in exon 7 (coding exon 7) of the ZNF414 gene. This alteration results from a C to T substitution at nucleotide position 1064, causing the proline (P) at amino acid position 355 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
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.6
DANN	Benign	0.80
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.081
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.019
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0050	D
Vest4		0.079
MVP		0.072
MPC		0.23
ClinPred		0.013	T
GERP RS		-0.055
gMVP		0.20
Mutation Taster		=90/10	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: rs576116806; hg19: chr19-8575770;