NM_145806.4:c.103C>T

Variant names:

• chr10-133309046-C-T
• rs1275603255
• NM_145806.4:c.103C>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.103C>T​(p.Arg35Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000889 in 1,124,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 8.9e-7 (0 hom.)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.233
• Publications: 1 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=0.12565005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.103C>T	p.Arg35Cys	missense_variant	Exon 1 of 6	ENST00000361518.10	NP_665805.2
TUBGCP2	NM_006659.4	c.-263G>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.103C>T	p.Arg35Cys	missense_variant	Exon 1 of 6	1	NM_145806.4	ENSP00000355251.5
TUBGCP2	ENST00000252936.8	c.-263G>A		upstream_gene_variant		2	NM_006659.4	ENSP00000252936.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 21096 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 8.89e-7 AC: 1 AN: 1124730 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 534158

African (AFR) AF: 0.00 AC: 0 AN: 23368

American (AMR) AF: 0.00 AC: 0 AN: 9006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14744

East Asian (EAS) AF: 0.00 AC: 0 AN: 27050

South Asian (SAS) AF: 0.00 AC: 0 AN: 26498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3500

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 938208

Other (OTH) AF: 0.00 AC: 0 AN: 45304

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103C>T (p.R35C) 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 103, causing the arginine (R) at amino acid position 35 to be replaced by a cysteine (C). 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	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		-0.23
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.050
Sift	Benign	0.082	T;T
Sift4G	Benign	0.083	T;T
Polyphen		0.027	B;.
Vest4		0.056
MutPred		0.41		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.067
MPC		0.50
ClinPred		0.29	T
GERP RS		0.90
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.35
Mutation Taster		=95/5	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

dbSNP: rs1275603255; hg19: chr10-135122550;