19-43597119-C-A

Variant names:

• chr19-43597119-C-A
• rs1342837087
• NM_001145347.2:c.11C>A

Variant summary

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

The NM_001145347.2(ZNF576):​c.11C>A​(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF576 NM_001145347.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.143

Genes affected

ZNF576 (HGNC:28357): (zinc finger protein 576) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and 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]

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

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=0.03187248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF576	NM_001145347.2	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 3	ENST00000336564.5	NP_001138819.1
ZNF576	NM_024327.2	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 3		NP_077303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF576	ENST00000336564.5	c.11C>A	p.Pro4Gln	missense_variant	Exon 2 of 3	1	NM_001145347.2	ENSP00000337852.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>A (p.P4Q) alteration is located in exon 2 (coding exon 1) of the ZNF576 gene. This alteration results from a C to A substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 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	0.069
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.4
DANN	Benign	0.86
DEOGEN2	Benign	0.0059	T;T;T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.38	.;.;.;.;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.032	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N;N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.32	T;T;T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B;B
Vest4		0.19
MutPred		0.23		Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);
MVP		0.22
MPC		0.62
ClinPred		0.044	T
GERP RS		-1.9
Varity_R		0.027
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1342837087; hg19: chr19-44101271;