19-58480356-C-T

Position:

• chr19-58480356-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_017908.4(ZNF446):​c.983C>T​(p.Pro328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,603,316 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (59 hom.)
• Consequence: ZNF446 NM_017908.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.46

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ZNF446 (HGNC:):

SLC27A5 (HGNC:10999): (solute carrier family 27 member 5) The protein encoded by this gene is an isozyme of very long-chain acyl-CoA synthetase (VLCS). It is capable of activating very long-chain fatty-acids containing 24- and 26-carbons. It is expressed in liver and associated with endoplasmic reticulum but not with peroxisomes. Its primary role is in fatty acid elongation or complex lipid synthesis rather than in degradation. This gene has a mouse ortholog. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044320524).
• BP6: Variant 19-58480356-C-T is Benign according to our data. Variant chr19-58480356-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2650591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4	c.983C>T	p.Pro328Leu	missense_variant	7/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1	c.802+337C>T		intron_variant			NP_001291382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6	c.983C>T	p.Pro328Leu	missense_variant	7/7	1	NM_017908.4	ENSP00000472802.1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152220 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00569 AC: 1290 AN: 226740 Hom.: 9 AF XY: 0.00612 AC XY: 756 AN XY: 123568

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00413

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00568

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00888

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00809 AC: 11745 AN: 1450980 Hom.: 59 Cov.: 34 AF XY: 0.00803 AC XY: 5788 AN XY: 720966

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00384

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00544

Gnomad4 FIN exome AF: 0.00246

Gnomad4 NFE exome AF: 0.00934

Gnomad4 OTH exome AF: 0.00746

GnomAD4 genome AF: 0.00465 AC: 708 AN: 152336 Hom.: 4 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74500

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00745

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00753 Hom.: 10

Bravo AF: 0.00492

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00563 AC: 682

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

ZNF446: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.62
DANN	Benign	0.95
DEOGEN2	Benign	0.073	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.69	T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;.;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.11
MVP		0.072
MPC		0.067
ClinPred		0.0027	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.042
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34732619; hg19: chr19-58991723;