19-7083112-T-C

Variant names:

• chr19-7083112-T-C
• rs549303729
• NM_024341.3:c.661T>C

Variant summary

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

The NM_024341.3(ZNF557):​c.661T>C​(p.Ser221Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ZNF557 NM_024341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0270

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=0.26078337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF557	NM_024341.3	c.661T>C	p.Ser221Pro	missense_variant	Exon 8 of 8	ENST00000252840.11	NP_077317.2
ZNF557	NM_001044387.2	c.661T>C	p.Ser221Pro	missense_variant	Exon 8 of 8		NP_001037852.1
ZNF557	NM_001044388.2	c.640T>C	p.Ser214Pro	missense_variant	Exon 8 of 8		NP_001037853.1
ZNF557	XM_047439432.1	c.640T>C	p.Ser214Pro	missense_variant	Exon 8 of 8		XP_047295388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF557	ENST00000252840.11	c.661T>C	p.Ser221Pro	missense_variant	Exon 8 of 8	1	NM_024341.3	ENSP00000252840.5
ZNF557	ENST00000414706.2	c.640T>C	p.Ser214Pro	missense_variant	Exon 8 of 8	2		ENSP00000404065.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250402 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727214

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: 0.0000936

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661T>C (p.S221P) alteration is located in exon 8 (coding exon 6) of the ZNF557 gene. This alteration results from a T to C substitution at nucleotide position 661, causing the serine (S) at amino acid position 221 to be replaced by a proline (P). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.11
Sift	Benign	0.030	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;D
Vest4		0.22
MutPred		0.63		.;Loss of catalytic residue at S214 (P = 0.0024);
MVP		0.45
MPC		0.36
ClinPred		0.35	T
GERP RS		1.1
Varity_R		0.52
gMVP		0.059

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: rs549303729; hg19: chr19-7083123;