NM_024702.3:c.1725A>G

Variant names:

• chr17-82830589-T-C
• rs12938126
• NM_024702.3:c.1725A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024702.3(ZNF750):​c.1725A>G​(p.Ala575Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,613,896 control chromosomes in the GnomAD database, including 132,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12309 hom., cov: 33)
  • Exomes 𝑓: 0.40 (120393 hom.)
• Consequence: ZNF750 NM_024702.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.256
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-82830589-T-C is Benign according to our data. Variant chr17-82830589-T-C is described in ClinVar as Benign. ClinVar VariationId is 1177929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.256 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 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.1725A>G	p.Ala575Ala	synonymous	Exon 3 of 3	NP_078978.2
	TBCD	NM_005993.5	MANE Select	c.1318+15655T>C		intron	N/A	NP_005984.3
	TBCD	NM_001411101.1		c.1267+15655T>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.1725A>G	p.Ala575Ala	synonymous	Exon 3 of 3	ENSP00000269394.3
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.1318+15655T>C		intron	N/A	ENSP00000347719.4
	ZNF750	ENST00000572562.1	TSL:2	c.528A>G	p.Ala176Ala	synonymous	Exon 3 of 3	ENSP00000458389.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60871 AN: 151978 Hom.: 12285 Cov.: 33

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.398

GnomAD2 exomes AF: 0.393 AC: 98688 AN: 251314 AF XY: 0.390

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.356

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.405 AC: 591557 AN: 1461800 Hom.: 120393 Cov.: 124 AF XY: 0.402 AC XY: 292294 AN XY: 727200

African (AFR) AF: 0.406 AC: 13589 AN: 33480

American (AMR) AF: 0.431 AC: 19255 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10060 AN: 26136

East Asian (EAS) AF: 0.368 AC: 14617 AN: 39700

South Asian (SAS) AF: 0.345 AC: 29739 AN: 86258

European-Finnish (FIN) AF: 0.396 AC: 21127 AN: 53334

Middle Eastern (MID) AF: 0.389 AC: 2245 AN: 5768

European-Non Finnish (NFE) AF: 0.411 AC: 456686 AN: 1112006

Other (OTH) AF: 0.401 AC: 24239 AN: 60394

GnomAD4 genome AF: 0.401 AC: 60930 AN: 152096 Hom.: 12309 Cov.: 33 AF XY: 0.399 AC XY: 29643 AN XY: 74352

African (AFR) AF: 0.404 AC: 16752 AN: 41488

American (AMR) AF: 0.422 AC: 6458 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1355 AN: 3470

East Asian (EAS) AF: 0.359 AC: 1851 AN: 5154

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4814

European-Finnish (FIN) AF: 0.395 AC: 4180 AN: 10588

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.403 AC: 27399 AN: 67978

Other (OTH) AF: 0.394 AC: 832 AN: 2114

Alfa AF: 0.398 Hom.: 5661

Bravo AF: 0.405

Asia WGS AF: 0.365 AC: 1271 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		-0.26
PromoterAI		0.046	Neutral
Mutation Taster		=100/0	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: rs12938126; hg19: chr17-80788465; COSMIC: COSV53961367;