rs58632700

Positions:

• chr19-58480634-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017908.4(ZNF446):​c.1261C>T​(p.Arg421Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,611,992 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R421Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: ZNF446 NM_017908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

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]

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005828321).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF446	NM_017908.4	c.1261C>T	p.Arg421Trp	missense_variant	7/7	ENST00000594369.6
ZNF446	NM_001304453.1	c.802+615C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF446	ENST00000594369.6	c.1261C>T	p.Arg421Trp	missense_variant	7/7	1	NM_017908.4	P1

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151658 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00970

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000475

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00101 AC: 250 AN: 246740 Hom.: 0 AF XY: 0.000772 AC XY: 104 AN XY: 134690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0128

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000521

Gnomad NFE exome AF: 0.0000631

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1460214 Hom.: 2 Cov.: 33 AF XY: 0.000336 AC XY: 244 AN XY: 726496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000481

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000376 AC: 57 AN: 151778 Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74184

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00953

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000475

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000578

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00106 AC: 128

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.56	N;N
PrimateAI	Uncertain	0.63	T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.30
MVP		0.20
MPC		0.40
ClinPred		0.28	T
GERP RS		3.1
Varity_R		0.31
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs58632700; hg19: chr19-58992001; COSMIC: COSV59991536; COSMIC: COSV59991536;