rs35653278

Positions:

• chr17-82831592-G-A
• chr17-82831592-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
ZNF750	NM_024702.3	c.863C>T	p.Pro288Leu	missense_variant	2/3	ENST00000269394.4	NP_078978.2
TBCD	NM_005993.5	c.1318+16658G>A		intron_variant		ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF750	ENST00000269394.4	c.863C>T	p.Pro288Leu	missense_variant	2/3	1	NM_024702.3	ENSP00000269394	P1
TBCD	ENST00000355528.9	c.1318+16658G>A		intron_variant		1	NM_005993.5	ENSP00000347719	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: no assertion criteria provided

Submissions by phenotype

ZNF750-related disorder Benign:1

Benign, no assertion criteria provided

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;