chr17-82830616-A-G

Variant names:

• chr17-82830616-A-G
• rs12948179
• NM_024702.3:c.1698T>C

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.1698T>C​(p.Pro566Pro) 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 1,613,826 control chromosomes in the GnomAD database, including 132,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12325 hom., cov: 33)
  • Exomes 𝑓: 0.40 (120462 hom.)
• Consequence: ZNF750 NM_024702.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.33
• Publications: 22 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=-0.92).
• BP6: Variant 17-82830616-A-G is Benign according to our data. Variant chr17-82830616-A-G is described in ClinVar as [Benign]. Clinvar id is 1178591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF750	NM_024702.3	c.1698T>C	p.Pro566Pro	synonymous_variant	Exon 3 of 3	ENST00000269394.4	NP_078978.2
TBCD	NM_005993.5	c.1318+15682A>G		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	c.1698T>C	p.Pro566Pro	synonymous_variant	Exon 3 of 3	1	NM_024702.3	ENSP00000269394.3
TBCD	ENST00000355528.9	c.1318+15682A>G		intron_variant	Intron 13 of 38	1	NM_005993.5	ENSP00000347719.4

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60928 AN: 151926 Hom.: 12303 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.391

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: 98715 AN: 251256 AF XY: 0.390

Gnomad AFR exome AF: 0.401

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: 591733 AN: 1461782 Hom.: 120462 Cov.: 118 AF XY: 0.402 AC XY: 292378 AN XY: 727188

African (AFR) AF: 0.407 AC: 13612 AN: 33480

American (AMR) AF: 0.430 AC: 19251 AN: 44724

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

East Asian (EAS) AF: 0.368 AC: 14624 AN: 39700

South Asian (SAS) AF: 0.345 AC: 29730 AN: 86258

European-Finnish (FIN) AF: 0.396 AC: 21137 AN: 53314

Middle Eastern (MID) AF: 0.389 AC: 2246 AN: 5768

European-Non Finnish (NFE) AF: 0.411 AC: 456829 AN: 1112008

Other (OTH) AF: 0.401 AC: 24244 AN: 60394

GnomAD4 genome AF: 0.401 AC: 60984 AN: 152044 Hom.: 12325 Cov.: 33 AF XY: 0.399 AC XY: 29669 AN XY: 74312

African (AFR) AF: 0.405 AC: 16789 AN: 41478

American (AMR) AF: 0.423 AC: 6458 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1853 AN: 5150

South Asian (SAS) AF: 0.344 AC: 1654 AN: 4814

European-Finnish (FIN) AF: 0.395 AC: 4182 AN: 10582

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

European-Non Finnish (NFE) AF: 0.403 AC: 27407 AN: 67958

Other (OTH) AF: 0.393 AC: 830 AN: 2110

Alfa AF: 0.404 Hom.: 28695

Bravo AF: 0.406

Asia WGS AF: 0.366 AC: 1273 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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.40
PhyloP100		-4.3
PromoterAI		-0.039	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: rs12948179; hg19: chr17-80788492; COSMIC: COSV53959157;