chr19-58479682-T-C

Position:

• chr19-58479682-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017908.4(ZNF446):​c.667T>C​(p.Tyr223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF446 NM_017908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22263452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4	c.667T>C	p.Tyr223His	missense_variant	5/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1	c.667T>C	p.Tyr223His	missense_variant	4/6		NP_001291382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6	c.667T>C	p.Tyr223His	missense_variant	5/7	1	NM_017908.4	ENSP00000472802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.667T>C (p.Y223H) alteration is located in exon 5 (coding exon 4) of the ZNF446 gene. This alteration results from a T to C substitution at nucleotide position 667, causing the tyrosine (Y) at amino acid position 223 to be replaced by a histidine (H). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.87	D;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.9	.;M;M
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.031	.;B;.
Vest4		0.23
MutPred		0.73		Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP		0.14
MPC		0.18
ClinPred		0.29	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr19-58991049;