19-55644710-C-T

Position:

• chr19-55644710-C-T

Variant summary

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

The NM_016535.4(ZNF581):​c.139C>T​(p.Pro47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ZNF581 NM_016535.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.46

Genes affected

ZNF581 (HGNC:25017): (zinc finger protein 581) Predicted to enable DNA-binding transcription factor activity 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CCDC106 (HGNC:30181): (coiled-coil domain containing 106) Located in cytosol and nucleoplasm. [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=0.03489408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF581	NM_016535.4	c.139C>T	p.Pro47Ser	missense_variant	2/2	ENST00000270451.6	NP_057619.1
ZNF581	XM_017026867.2	c.139C>T	p.Pro47Ser	missense_variant	2/2		XP_016882356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF581	ENST00000270451.6	c.139C>T	p.Pro47Ser	missense_variant	2/2	1	NM_016535.4	ENSP00000270451.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 18, 2022

The c.139C>T (p.P47S) alteration is located in exon 2 (coding exon 1) of the ZNF581 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the proline (P) at amino acid position 47 to be replaced by a serine (S). 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	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.0
DANN	Benign	0.88
DEOGEN2	Benign	0.022	T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.50	.;T;.;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	N;.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.22	.;.;N;.
REVEL	Benign	0.011
Sift	Benign	1.0	.;.;T;.
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.065
MutPred		0.28		Loss of catalytic residue at P47 (P = 0.0054);Loss of catalytic residue at P47 (P = 0.0054);Loss of catalytic residue at P47 (P = 0.0054);Loss of catalytic residue at P47 (P = 0.0054);
MVP		0.081
MPC		0.68
ClinPred		0.028	T
GERP RS		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.019
gMVP		0.17

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: rs1982747766; hg19: chr19-56156076;