19-58433721-C-G

Position:

• chr19-58433721-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003433.4(ZNF132):​c.1723G>C​(p.Glu575Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,612,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: ZNF132 NM_003433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.74

Genes affected

ZNF132 (HGNC:12916): (zinc finger protein 132) 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]

ZNF324B (HGNC:33107): (zinc finger protein 324B) 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017493874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF132	NM_003433.4	c.1723G>C	p.Glu575Gln	missense_variant	3/3	ENST00000254166.4	NP_003424.3
ZNF132	XM_047439361.1	c.1684G>C	p.Glu562Gln	missense_variant	3/3		XP_047295317.1
ZNF324B	XM_047438807.1	c.-5-5720C>G		intron_variant			XP_047294763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF132	ENST00000254166.4	c.1723G>C	p.Glu575Gln	missense_variant	3/3	1	NM_003433.4	ENSP00000254166.2
ZNF132	ENST00000599148.1	n.1864G>C		non_coding_transcript_exon_variant	1/1	6
ZNF132	ENST00000703732.1	n.2189G>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000493 AC: 124 AN: 251390 Hom.: 1 AF XY: 0.000420 AC XY: 57 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1460160 Hom.: 1 Cov.: 30 AF XY: 0.000654 AC XY: 475 AN XY: 726382

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000816

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74444

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000545

EpiControl AF: 0.000830

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

Jun 22, 2021

The c.1723G>C (p.E575Q) alteration is located in exon 3 (coding exon 3) of the ZNF132 gene. This alteration results from a G to C substitution at nucleotide position 1723, causing the glutamic acid (E) at amino acid position 575 to be replaced by a glutamine (Q). 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	0.17
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.00079	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.095	N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.036
Sift	Uncertain	0.0050	D;.
Sift4G	Benign	0.22	T;.
Polyphen		0.012	B;.
Vest4		0.077
MVP		0.085
MPC		0.013
ClinPred		0.033	T
GERP RS		-4.7
Varity_R		0.21
gMVP		0.044

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: rs147275148; hg19: chr19-58945088;