dbSNP rs34687659: ZNF750:p.Gln392Arg (chr17-82831280-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024702.3(ZNF750):c.1175A>G(p.Gln392Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,613,872 control chromosomes in the GnomAD database, including 755 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.039 ( 404 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 351 hom. )

Consequence

ZNF750
NM_024702.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.741

Publications

9 publications found

Variant links:

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]

ZNF750 links:

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)

TBCD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024068952).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF750	NM_024702.3 link	c.1175A>G	p.Gln392Arg	missense_variant	Exon 2 of 3	ENST00000269394.4	NP_078978.2
TBCD	NM_005993.5 link	c.1318+16346T>C		intron_variant	Intron 13 of 38	ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF750	ENST00000269394.4 link	c.1175A>G	p.Gln392Arg	missense_variant	Exon 2 of 3	1	NM_024702.3	ENSP00000269394.3
TBCD	ENST00000355528.9 link	c.1318+16346T>C		intron_variant	Intron 13 of 38	1	NM_005993.5	ENSP00000347719.4

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5923

AN:

152182

Hom.:

393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.00998

AC:

2505

AN:

251126

AF XY:

0.00693

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00413

AC:

6032

AN:

1461572

Hom.:

351

Cov.:

AF XY:

0.00360

AC XY:

2614

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.142

AC:

4747

AN:

33478

American (AMR)

AF:

0.00747

AC:

334

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000441

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53108

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000297

AC:

330

AN:

1112008

Other (OTH)

AF:

0.00883

AC:

533

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

402

804

1205

1607

2009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0392

AC:

5971

AN:

152300

Hom.:

404

Cov.:

AF XY:

0.0385

AC XY:

2869

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.134

AC:

5586

AN:

41556

American (AMR)

AF:

0.0188

AC:

287

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68022

Other (OTH)

AF:

0.0265

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

253

505

758

1010

1263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0142

Hom.:

250

Bravo

AF:

0.0448

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.131

AC:

578

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0127

AC:

1547

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.74

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Benign

0.062

Sift

Benign

0.18

Sift4G

Benign

0.29

Polyphen

0.49

Vest4

0.040

MPC

0.24

ClinPred

0.0057

GERP RS

1.9

Varity_R

0.073

gMVP

0.22

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over