10-133309399-G-C

Variant names:

• chr10-133309399-G-C
• rs763138340
• NM_145806.4:c.163G>C

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.163G>C​(p.Val55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V55M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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=0.23637551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.163G>C	p.Val55Leu	missense_variant	Exon 2 of 6	ENST00000361518.10	NP_665805.2
ZNF511-PRAP1	NM_001396060.1	c.163G>C	p.Val55Leu	missense_variant	Exon 2 of 9		NP_001382989.1
ZNF511	NR_130127.2	n.193G>C		non_coding_transcript_exon_variant	Exon 2 of 6
TUBGCP2	NR_046330.2	n.718+2221C>G		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF511	ENST00000361518.10	c.163G>C	p.Val55Leu	missense_variant	Exon 2 of 6	1	NM_145806.4	ENSP00000355251.5
ZNF511-PRAP1	ENST00000368554.8	c.-12G>C		upstream_gene_variant		2		ENSP00000357542.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459400 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725942

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111546

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		1.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.081
Sift	Benign	0.15	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.80	P;.
Vest4		0.46
MutPred		0.28		Gain of catalytic residue at V55 (P = 0.0662);Gain of catalytic residue at V55 (P = 0.0662);
MVP		0.040
MPC		0.62
ClinPred		0.84	D
GERP RS		2.6
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs763138340; hg19: chr10-135122903;