chr10-133309082-C-T

Variant names:

• chr10-133309082-C-T
• NM_145806.4:c.139C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145806.4(ZNF511):​c.139C>T​(p.His47Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

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:38088): (ZNF511-PRAP1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ZNF511 (zinc finger protein 511) and PRAP1 (proline-rich acidic protein 1) genes on chromosome 10. The putative readthrough transcript may encode a fusion protein that shares sequence identity with each individual gene product and may be involved in the regulation of gene promoters, particularly those found on transfected plasmids. [provided by RefSeq, Apr 2017]

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]

TUBGCP2 Gene-Disease associations (from GenCC):

• Norman-Roberts syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24245915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.139C>T	p.His47Tyr	missense_variant	Exon 1 of 6	ENST00000361518.10	NP_665805.2
TUBGCP2	NM_006659.4	c.-299G>A		upstream_gene_variant		ENST00000252936.8	NP_006650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF511	ENST00000361518.10	c.139C>T	p.His47Tyr	missense_variant	Exon 1 of 6	1	NM_145806.4	ENSP00000355251.5
TUBGCP2	ENST00000252936.8	c.-299G>A		upstream_gene_variant		2	NM_006659.4	ENSP00000252936.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1156088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 551902

African (AFR) AF: 0.00 AC: 0 AN: 24398

American (AMR) AF: 0.00 AC: 0 AN: 11386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15204

East Asian (EAS) AF: 0.00 AC: 0 AN: 29044

South Asian (SAS) AF: 0.00 AC: 0 AN: 30968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3892

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 955914

Other (OTH) AF: 0.00 AC: 0 AN: 46580

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>T (p.H47Y) alteration is located in exon 1 (coding exon 1) of the ZNF511 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the histidine (H) at amino acid position 47 to be replaced by a tyrosine (Y). 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	0.58
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.045
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.079
Sift	Benign	0.062	T;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.24
MutPred		0.34		Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);
MVP		0.15
MPC		1.2
ClinPred		0.97	D
GERP RS		2.8
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.32
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr10-135122586;