19-7519250-G-A

Position:

• chr19-7519250-G-A

Variant summary

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

The NM_018083.5(ZNF358):​c.8G>A​(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF358 NM_018083.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

ZNF358 (HGNC:16838): (zinc finger protein 358) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in several processes, including embryonic forelimb morphogenesis; neural tube development; and stem cell population maintenance. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LOC105372261 (HGNC:):

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=0.19957551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF358	NM_018083.5	c.8G>A	p.Arg3His	missense_variant	2/2	ENST00000597229.2	NP_060553.4
LOC105372261	XR_936294.3	n.936+3592C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF358	ENST00000597229.2	c.8G>A	p.Arg3His	missense_variant	2/2	2	NM_018083.5	ENSP00000472305	P1
ZNF358	ENST00000596712.1	c.8G>A	p.Arg3His	missense_variant	2/2	3		ENSP00000472777

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461174 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

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

Jul 20, 2021

The c.8G>A (p.R3H) alteration is located in exon 2 (coding exon 1) of the ZNF358 gene. This alteration results from a G to A substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 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	Benign	0.28
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T
MutationTaster	Benign	0.97	N
MVP		0.072
ClinPred		0.66	D
GERP RS		3.4

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: rs1392603082; hg19: chr19-7584136;