chr19-7083083-A-T

Position:

• chr19-7083083-A-T

Variant summary

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

The NM_024341.3(ZNF557):​c.632A>T​(p.Asn211Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNF557 NM_024341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.00

Genes affected

ZNF557 (HGNC:28632): (zinc finger protein 557) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.07292101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF557	NM_024341.3	c.632A>T	p.Asn211Ile	missense_variant	8/8	ENST00000252840.11	NP_077317.2
ZNF557	NM_001044387.2	c.632A>T	p.Asn211Ile	missense_variant	8/8		NP_001037852.1
ZNF557	NM_001044388.2	c.611A>T	p.Asn204Ile	missense_variant	8/8		NP_001037853.1
ZNF557	XM_047439432.1	c.611A>T	p.Asn204Ile	missense_variant	8/8		XP_047295388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF557	ENST00000252840.11	c.632A>T	p.Asn211Ile	missense_variant	8/8	1	NM_024341.3	ENSP00000252840.5
ZNF557	ENST00000414706.2	c.611A>T	p.Asn204Ile	missense_variant	8/8	2		ENSP00000404065.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727202

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 01, 2023

The c.632A>T (p.N211I) alteration is located in exon 8 (coding exon 6) of the ZNF557 gene. This alteration results from a A to T substitution at nucleotide position 632, causing the asparagine (N) at amino acid position 211 to be replaced by an isoleucine (I). 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	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.9
DANN	Benign	0.95
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Benign	0.090
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.023	D;D
Polyphen		0.041	B;B
Vest4		0.31
MutPred		0.41		.;Loss of disorder (P = 0.0322);
MVP		0.15
MPC		0.088
ClinPred		0.16	T
GERP RS		-1.1
Varity_R		0.18
gMVP		0.050

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: rs751657962; hg19: chr19-7083094;