17-82831752-T-C

Variant names:

• chr17-82831752-T-C
• rs8074277
• NM_024702.3:c.703A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 30 publications found

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]

TBCD Gene-Disease associations (from GenCC):

• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024702.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF750	NM_024702.3	MANE Select	c.703A>G	p.Met235Val	missense	Exon 2 of 3	NP_078978.2
	TBCD	NM_005993.5	MANE Select	c.1318+16818T>C		intron	N/A	NP_005984.3
	TBCD	NM_001411101.1		c.1267+16818T>C		intron	N/A	NP_001398030.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF750	ENST00000269394.4	TSL:1 MANE Select	c.703A>G	p.Met235Val	missense	Exon 2 of 3	ENSP00000269394.3
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.1318+16818T>C		intron	N/A	ENSP00000347719.4
	TBCD	ENST00000684760.1		c.1318+16818T>C		intron	N/A	ENSP00000507696.1

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

GnomAD2 exomes AF: 0.175 AC: 43914 AN: 251358 AF XY: 0.165

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 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

African (AFR) AF: 0.132 AC: 4409 AN: 33480

American (AMR) AF: 0.285 AC: 12730 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3595 AN: 26136

East Asian (EAS) AF: 0.0738 AC: 2928 AN: 39700

South Asian (SAS) AF: 0.0584 AC: 5037 AN: 86258

European-Finnish (FIN) AF: 0.235 AC: 12562 AN: 53412

Middle Eastern (MID) AF: 0.107 AC: 619 AN: 5768

European-Non Finnish (NFE) AF: 0.178 AC: 198449 AN: 1112000

Other (OTH) AF: 0.163 AC: 9831 AN: 60396

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

African (AFR) AF: 0.134 AC: 5545 AN: 41412

American (AMR) AF: 0.232 AC: 3545 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3466

East Asian (EAS) AF: 0.0826 AC: 427 AN: 5172

South Asian (SAS) AF: 0.0473 AC: 228 AN: 4824

European-Finnish (FIN) AF: 0.231 AC: 2441 AN: 10546

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.182 AC: 12377 AN: 67964

Other (OTH) AF: 0.149 AC: 314 AN: 2106

Alfa AF: 0.170 Hom.: 10105

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

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
PhyloP100		-2.1
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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