chr17-82830344-G-C

Position:

• chr17-82830344-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_024702.3(ZNF750):​c.1970C>G​(p.Ala657Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,688 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ZNF750 NM_024702.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.308

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049552023).
• BP6: Variant 17-82830344-G-C is Benign according to our data. Variant chr17-82830344-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 720410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF750	NM_024702.3	c.1970C>G	p.Ala657Gly	missense_variant	3/3	ENST00000269394.4
TBCD	NM_005993.5	c.1318+15410G>C		intron_variant		ENST00000355528.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF750	ENST00000269394.4	c.1970C>G	p.Ala657Gly	missense_variant	3/3	1	NM_024702.3	P1
TBCD	ENST00000355528.9	c.1318+15410G>C		intron_variant		1	NM_005993.5	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000542 AC: 136 AN: 250998 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135718

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461324 Hom.: 1 Cov.: 31 AF XY: 0.000290 AC XY: 211 AN XY: 727012

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000413 AC: 63 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74510

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000648 Hom.: 0

Bravo AF: 0.000506

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.1970C>G (p.A657G) alteration is located in exon 3 (coding exon 2) of the ZNF750 gene. This alteration results from a C to G substitution at nucleotide position 1970, causing the alanine (A) at amino acid position 657 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.091
DANN	Benign	0.63
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.014
Sift	Benign	0.37	T;.
Sift4G	Benign	0.38	T;T
Polyphen		0.0050	B;.
Vest4		0.092
MVP		0.043
MPC		0.23
ClinPred		0.00084	T
GERP RS		-0.68
Varity_R		0.053
gMVP		0.037

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: rs61729341; hg19: chr17-80788220;