10-133308952-G-C

Variant names:

• chr10-133308952-G-C
• rs927776215
• NM_145806.4:c.9G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_145806.4(ZNF511):​c.9G>C​(p.Leu3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,233,598 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2211541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.9G>C	p.Leu3Phe	missense_variant	Exon 1 of 6	ENST00000361518.10	NP_665805.2
TUBGCP2	NM_006659.4	c.-169C>G		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.9G>C	p.Leu3Phe	missense_variant	Exon 1 of 6	1	NM_145806.4	ENSP00000355251.5
TUBGCP2	ENST00000252936.8	c.-169C>G		upstream_gene_variant		2	NM_006659.4	ENSP00000252936.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151768 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000333 AC: 36 AN: 1081830 Hom.: 0 Cov.: 30 AF XY: 0.0000431 AC XY: 22 AN XY: 510938

African (AFR) AF: 0.000133 AC: 3 AN: 22504

American (AMR) AF: 0.000124 AC: 1 AN: 8038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13832

East Asian (EAS) AF: 0.000272 AC: 7 AN: 25698

South Asian (SAS) AF: 0.00 AC: 0 AN: 20058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2862

European-Non Finnish (NFE) AF: 0.0000263 AC: 24 AN: 914184

Other (OTH) AF: 0.0000233 AC: 1 AN: 42990

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151768 Hom.: 0 Cov.: 34 AF XY: 0.0000405 AC XY: 3 AN XY: 74150

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.0000656 AC: 1 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67834

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.7
DANN	Benign	0.90
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		-0.087
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.10
Sift	Benign	0.036	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.23
MutPred		0.28		Loss of glycosylation at P5 (P = 0.1591);Loss of glycosylation at P5 (P = 0.1591);
MVP		0.030
MPC		0.39
ClinPred		0.23	T
GERP RS		1.0
PromoterAI		0.19	Neutral
Varity_R		0.041
gMVP		0.40
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs927776215; hg19: chr10-135122456;