10-133308992-G-A

Variant names:

• chr10-133308992-G-A
• NM_145806.4:c.49G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145806.4(ZNF511):​c.49G>A​(p.Ala17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0270
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055247813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.49G>A	p.Ala17Thr	missense_variant	Exon 1 of 6	ENST00000361518.10	NP_665805.2
TUBGCP2	NM_006659.4	c.-209C>T		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.49G>A	p.Ala17Thr	missense_variant	Exon 1 of 6	1	NM_145806.4	ENSP00000355251.5
TUBGCP2	ENST00000252936.8	c.-209C>T		upstream_gene_variant		2	NM_006659.4	ENSP00000252936.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095260 Hom.: 0 Cov.: 30 AF XY: 0.00000193 AC XY: 1 AN XY: 517620

African (AFR) AF: 0.00 AC: 0 AN: 22814

American (AMR) AF: 0.00 AC: 0 AN: 8330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14244

East Asian (EAS) AF: 0.00 AC: 0 AN: 26378

South Asian (SAS) AF: 0.00 AC: 0 AN: 21104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2936

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 920548

Other (OTH) AF: 0.00 AC: 0 AN: 43720

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49G>A (p.A17T) alteration is located in exon 1 (coding exon 1) of the ZNF511 gene. This alteration results from a G to A substitution at nucleotide position 49, causing the alanine (A) at amino acid position 17 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PhyloP100		0.027
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.045
Sift	Benign	0.18	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;.
Vest4		0.028
MutPred		0.14		Gain of glycosylation at A17 (P = 0.0095);Gain of glycosylation at A17 (P = 0.0095);
MVP		0.014
MPC		0.35
ClinPred		0.057	T
GERP RS		-0.64
PromoterAI		0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.23
Mutation Taster		=99/1	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: chr10-135122496;