chrX-153421519-C-T

Position:

• chrX-153421519-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001136273.2(ZFP92):​c.1142C>T​(p.Ala381Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,135,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 7 hem., cov: 26)
  • Exomes 𝑓: 0.00024 (0 hom. 95 hem.)
• Consequence: ZFP92 NM_001136273.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.545

Genes affected

ZFP92 (HGNC:12865): (ZFP92 zinc finger protein) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066350102).
• BP6: Variant X-153421519-C-T is Benign according to our data. Variant chrX-153421519-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2354909.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFP92	NM_001136273.2	c.1142C>T	p.Ala381Val	missense_variant	6/6	ENST00000338647.7
ZFP92	NM_001386944.1	c.1142C>T	p.Ala381Val	missense_variant	5/5
ZFP92	NM_001386945.1	c.1142C>T	p.Ala381Val	missense_variant	7/7
ZFP92	NM_001386943.1	c.1016C>T	p.Ala339Val	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP92	ENST00000338647.7	c.1142C>T	p.Ala381Val	missense_variant	6/6	5	NM_001136273.2	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 35 AN: 113449 Hom.: 0 Cov.: 26 AF XY: 0.000224 AC XY: 8 AN XY: 35729

Gnomad AFR AF: 0.0000955

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000734

Gnomad ASJ AF: 0.000752

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000306 AC: 24 AN: 78365 Hom.: 0 AF XY: 0.000280 AC XY: 7 AN XY: 25029

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000304

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.000237 AC: 242 AN: 1021859 Hom.: 0 Cov.: 31 AF XY: 0.000289 AC XY: 95 AN XY: 329253

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000194

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000833

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.000394

GnomAD4 genome AF: 0.000300 AC: 34 AN: 113495 Hom.: 0 Cov.: 26 AF XY: 0.000196 AC XY: 7 AN XY: 35785

Gnomad4 AFR AF: 0.0000953

Gnomad4 AMR AF: 0.000733

Gnomad4 ASJ AF: 0.000752

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000394

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000803 Hom.: 5

Bravo AF: 0.000325

ExAC AF: 0.000249 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.1142C>T (p.A381V) alteration is located in exon 4 (coding exon 4) of the ZFP92 gene. This alteration results from a C to T substitution at nucleotide position 1142, causing the alanine (A) at amino acid position 381 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ZFP92-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.73
DANN	Benign	0.78
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0066	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0080	B
Vest4		0.024
MVP		0.082
MPC		1.0
GERP RS		0.31
Varity_R		0.024
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782495626; hg19: chrX-152686977; COSMIC: COSV58598992;