17-82830296-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024702.3(ZNF750):c.2018T>A(p.Met673Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,116 control chromosomes in the GnomAD database, including 1 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M673V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: ZNF750 NM_024702.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.178

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033802986).
• BP6: Variant 17-82830296-A-T is Benign according to our data. Variant chr17-82830296-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 727854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF750	NM_024702.3	c.2018T>A	p.Met673Lys	missense_variant	3/3	ENST00000269394.4
TBCD	NM_005993.5	c.1318+15362A>T		intron_variant		ENST00000355528.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF750	ENST00000269394.4	c.2018T>A	p.Met673Lys	missense_variant	3/3	1	NM_024702.3	P1
TBCD	ENST00000355528.9	c.1318+15362A>T		intron_variant		1	NM_005993.5	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251468 Hom.: 1 AF XY: 0.000324 AC XY: 44 AN XY: 135906

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461860 Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 727224

Gnomad4 AFR exome AF: 0.00460

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74424

Gnomad4 AFR AF: 0.00453

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.00154

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.0080
Dann	Benign	0.62
DEOGEN2	Benign	0.00034	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.28	N;.
REVEL	Benign	0.0080
Sift	Benign	0.40	T;.
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;.
Vest4		0.091
MVP		0.043
MPC		0.32
ClinPred		0.0029	T
GERP RS		-6.6
Varity_R		0.11
gMVP		0.056

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: rs147314418; hg19: chr17-80788172;