10-133309864-G-T

Variant names:

• chr10-133309864-G-T
• rs1057353840
• NM_145806.4:c.316G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145806.4(ZNF511):​c.316G>T​(p.Gly106*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF511 NM_145806.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF511	NM_145806.4	c.316G>T	p.Gly106*	stop_gained	Exon 3 of 6	ENST00000361518.10	NP_665805.2
ZNF511-PRAP1	NM_001396060.1	c.316G>T	p.Gly106*	stop_gained	Exon 3 of 9		NP_001382989.1
ZNF511	NR_130127.2	n.346G>T		non_coding_transcript_exon_variant	Exon 3 of 6
TUBGCP2	NR_046330.2	n.718+1756C>A		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF511	ENST00000361518.10	c.316G>T	p.Gly106*	stop_gained	Exon 3 of 6	1	NM_145806.4	ENSP00000355251.5
ZNF511-PRAP1	ENST00000368554.8	c.142G>T	p.Gly48*	stop_gained	Exon 2 of 8	2		ENSP00000357542.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	31
DANN	Benign	0.93
Eigen	Benign	-0.67
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
PhyloP100		-1.4
Vest4		0.34
GERP RS		-10
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=15/185	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 24

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

Other links and lift over

dbSNP: rs1057353840; hg19: chr10-135123368; COSMIC: COSV62919677; COSMIC: COSV62919677;