19-9653274-G-A

Variant names:

• chr19-9653274-G-A
• rs199722422
• NM_001130031.2:c.956C>T

Variant summary

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

The NM_001130031.2(ZNF562):​c.956C>T​(p.Thr319Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,614,022 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: ZNF562 NM_001130031.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.61

Genes affected

ZNF562 (HGNC:25950): (zinc finger protein 562) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF561-AS1 (HGNC:27613): (ZNF561 antisense RNA 1 (head to head))

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042236865).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF562	NM_001130031.2	c.956C>T	p.Thr319Met	missense_variant	Exon 6 of 6	ENST00000453372.7	NP_001123503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF562	ENST00000453372.7	c.956C>T	p.Thr319Met	missense_variant	Exon 6 of 6	3	NM_001130031.2	ENSP00000410734.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251374 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135862

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000241 AC: 352 AN: 1461876 Hom.: 2 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 727236

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74316

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000412

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.956C>T (p.T319M) alteration is located in exon 6 (coding exon 5) of the ZNF562 gene. This alteration results from a C to T substitution at nucleotide position 956, causing the threonine (T) at amino acid position 319 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.54	N;N;.
REVEL	Benign	0.031
Sift	Uncertain	0.0050	D;T;.
Sift4G	Uncertain	0.026	D;T;T
Polyphen		0.99	D;D;.
Vest4		0.22
MVP		0.13
ClinPred		0.020	T
GERP RS		-0.96
Varity_R		0.011
gMVP		0.064

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: rs199722422; hg19: chr19-9763950; COSMIC: COSV53333047; COSMIC: COSV53333047;