10-133308962-C-A

Variant summary

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

The NM_145806.4(ZNF511):c.19C>A(p.Leu7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,240,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.179

Genes affected

ZNF511 (HGNC:28445): (zinc finger protein 511) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ZNF511-PRAP1 (HGNC:):

TUBGCP2 (HGNC:18599): (tubulin gamma complex component 2) Predicted to enable gamma-tubulin binding activity. Predicted to contribute to microtubule minus-end binding activity. Involved in brain development and neuron migration. Located in centrosome 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=0.0045891106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF511	NM_145806.4	c.19C>A	p.Leu7Met	missense_variant	1/6	ENST00000361518.10
ZNF511-PRAP1	NM_001396060.1	c.19C>A	p.Leu7Met	missense_variant	1/9
ZNF511	NR_130127.2	n.49C>A		non_coding_transcript_exon_variant	1/6
TUBGCP2	NR_046330.2	n.718+2658G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF511	ENST00000361518.10	c.19C>A	p.Leu7Met	missense_variant	1/6	1	NM_145806.4	P1

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 151874 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000722

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000595 AC: 5 AN: 8398 Hom.: 0 AF XY: 0.000979 AC XY: 4 AN XY: 4084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000254

Gnomad NFE exome AF: 0.00718

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000422 AC: 459 AN: 1088268 Hom.: 1 Cov.: 30 AF XY: 0.000453 AC XY: 233 AN XY: 514238

Gnomad4 AFR exome AF: 0.0000442

Gnomad4 AMR exome AF: 0.000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00411

Gnomad4 FIN exome AF: 0.000239

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.000578

GnomAD4 genome AF: 0.000520 AC: 79 AN: 151982 Hom.: 0 Cov.: 34 AF XY: 0.000713 AC XY: 53 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000722

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000378

ExAC AF: 0.000150 AC: 2

Asia WGS AF: 0.000580 AC: 2 AN: 3458

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

Feb 16, 2023

The c.19C>A (p.L7M) alteration is located in exon 1 (coding exon 1) of the ZNF511 gene. This alteration results from a C to A substitution at nucleotide position 19, causing the leucine (L) at amino acid position 7 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	0.33
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.083
Sift	Benign	0.052	T;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.75	P;.
Vest4		0.40
MutPred		0.32		Gain of catalytic residue at L7 (P = 0.0722);Gain of catalytic residue at L7 (P = 0.0722);
MVP		0.030
MPC		0.35
ClinPred		0.061	T
GERP RS		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.086
gMVP		0.32

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: rs752943294; hg19: chr10-135122466;