10-133309883-G-C

Variant names:

• chr10-133309883-G-C
• rs1847948747
• NM_145806.4:c.335G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_145806.4(ZNF511):​c.335G>C​(p.Cys112Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF511 NM_145806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.335G>C	p.Cys112Ser	missense_variant	Exon 3 of 6	ENST00000361518.10	NP_665805.2
ZNF511-PRAP1	NM_001396060.1	c.335G>C	p.Cys112Ser	missense_variant	Exon 3 of 9		NP_001382989.1
ZNF511	NR_130127.2	n.365G>C		non_coding_transcript_exon_variant	Exon 3 of 6
TUBGCP2	NR_046330.2	n.718+1737C>G		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF511	ENST00000361518.10	c.335G>C	p.Cys112Ser	missense_variant	Exon 3 of 6	1	NM_145806.4	ENSP00000355251.5
ZNF511-PRAP1	ENST00000368554.8	c.161G>C	p.Cys54Ser	missense_variant	Exon 2 of 8	2		ENSP00000357542.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335G>C (p.C112S) alteration is located in exon 3 (coding exon 3) of the ZNF511 gene. This alteration results from a G to C substitution at nucleotide position 335, causing the cysteine (C) at amino acid position 112 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.3	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.90		Gain of disorder (P = 0.0073);Gain of disorder (P = 0.0073);
MVP		0.80
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1847948747; hg19: chr10-135123387;