17-82831752-T-C

Position:

• chr17-82831752-T-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.703A>G​(p.Met235Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,822 control chromosomes in the GnomAD database, including 25,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.17 (2331 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22897 hom.)
• Consequence: ZNF750 NM_024702.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.11

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=0.0019102395).
• BP6: Variant 17-82831752-T-C is Benign according to our data. Variant chr17-82831752-T-C is described in ClinVar as [Benign]. Clinvar id is 3060121.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF750	NM_024702.3	c.703A>G	p.Met235Val	missense_variant	2/3	ENST00000269394.4	NP_078978.2
TBCD	NM_005993.5	c.1318+16818T>C		intron_variant		ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF750	ENST00000269394.4	c.703A>G	p.Met235Val	missense_variant	2/3	1	NM_024702.3	ENSP00000269394	P1
TBCD	ENST00000355528.9	c.1318+16818T>C		intron_variant		1	NM_005993.5	ENSP00000347719	P1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25600 AN: 151834 Hom.: 2328 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0824

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.175 AC: 43914 AN: 251358 Hom.: 4573 AF XY: 0.165 AC XY: 22479 AN XY: 135882

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.0824

Gnomad SAS exome AF: 0.0578

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.171 AC: 250160 AN: 1461870 Hom.: 22897 Cov.: 38 AF XY: 0.168 AC XY: 121883 AN XY: 727236

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.0584

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.169 AC: 25620 AN: 151952 Hom.: 2331 Cov.: 32 AF XY: 0.169 AC XY: 12514 AN XY: 74262

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0826

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.149

Alfa AF: 0.166 Hom.: 5456

Bravo AF: 0.170

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.172 AC: 662

ESP6500AA AF: 0.131 AC: 577

ESP6500EA AF: 0.178 AC: 1534

ExAC AF: 0.169 AC: 20541

Asia WGS AF: 0.0610 AC: 215 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.158

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

Oct 28, 2019

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	0.054
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0020
DANN	Benign	0.53
DEOGEN2	Benign	0.00092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.22	N
MutationTaster	Benign	0.98	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.034
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.019
MPC		0.21
ClinPred		0.0077	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.13

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: rs8074277; hg19: chr17-80789628; COSMIC: COSV53960502;