rs35653278

chr17-82831592-G-Achr17-82831592-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024702.3(ZNF750):c.863C>T(p.Pro288Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0902 in 1,614,130 control chromosomes in the GnomAD database, including 7,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (560 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7301 hom.)
• Consequence: ZNF750 NM_024702.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.28

Genes affected

ZNF750 (HGNC:25843): (zinc finger protein 750) This gene encodes a protein with a nuclear localization site and a C2H2 zinc finger domain. Mutations in this gene have been associated with seborrhea-like dermatitis with psoriasiform elements. [provided by RefSeq, Jul 2008]

TBCD (HGNC:11581): (tubulin folding cofactor D) Cofactor D is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017530024).
• BP6: Variant 17-82831592-G-A is Benign according to our data. Variant chr17-82831592-G-A is described in ClinVar as [Benign]. Clinvar id is 3060437.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF750	NM_024702.3	c.863C>T	p.Pro288Leu	missense_variant	2/3	ENST00000269394.4
TBCD	NM_005993.5	c.1318+16658G>A		intron_variant		ENST00000355528.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF750	ENST00000269394.4	c.863C>T	p.Pro288Leu	missense_variant	2/3	1	NM_024702.3	P1
TBCD	ENST00000355528.9	c.1318+16658G>A		intron_variant		1	NM_005993.5	P1

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10564 AN: 152120 Hom.: 561 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0685 AC: 17232 AN: 251484 Hom.: 936 AF XY: 0.0683 AC XY: 9282 AN XY: 135914

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00898

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0712

GnomAD4 exome AF: 0.0924 AC: 135070 AN: 1461892 Hom.: 7301 Cov.: 37 AF XY: 0.0901 AC XY: 65561 AN XY: 727246

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.0285

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00875

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0789

GnomAD4 genome AF: 0.0694 AC: 10562 AN: 152238 Hom.: 560 Cov.: 32 AF XY: 0.0692 AC XY: 5149 AN XY: 74436

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.0380

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0910 Hom.: 1178

Bravo AF: 0.0589

TwinsUK AF: 0.103 AC: 382

ALSPAC AF: 0.0999 AC: 385

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.105 AC: 904

ExAC AF: 0.0703 AC: 8536

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0921

EpiControl AF: 0.0858

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNF750-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.13
Sift	Benign	0.038	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.21
ClinPred		0.026	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.065
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs35653278; hg19: chr17-80789468; COSMIC: COSV53958239;