Genetic Variant TFAP2D:p.Asn93Lys (chr6-50715355-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_172238.4(TFAP2D):c.279C>A(p.Asn93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TFAP2D
NM_172238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Variant links:

Genes affected

TFAP2D (HGNC:15581): (transcription factor AP-2 delta) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure development; regulation of cell population proliferation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within inferior colliculus development; negative regulation of neuron apoptotic process; and positive regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TFAP2D links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2D	NM_172238.4 link	c.279C>A	p.Asn93Lys	missense_variant	Exon 2 of 8	ENST00000008391.4	NP_758438.2	Q7Z6R9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2D	ENST00000008391.4 link	c.279C>A	p.Asn93Lys	missense_variant	Exon 2 of 8	1	NM_172238.4	ENSP00000008391.4		Q7Z6R9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.279C>A (p.N93K) alteration is located in exon 2 (coding exon 2) of the TFAP2D gene. This alteration results from a C to A substitution at nucleotide position 279, causing the asparagine (N) at amino acid position 93 to be replaced by a lysine (K). 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

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.049

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.022

Polyphen

0.60

Vest4

0.85

MutPred

0.59

Gain of methylation at N93 (P = 0.0079);

MVP

0.082

MPC

0.45

ClinPred

0.88

GERP RS

4.2

Varity_R

0.56

gMVP

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over