6-50715489-A-T

Variant names:

• chr6-50715489-A-T
• NM_172238.4:c.413A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_172238.4(TFAP2D):​c.413A>T​(p.Asp138Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TFAP2D NM_172238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2D	NM_172238.4	c.413A>T	p.Asp138Val	missense_variant	Exon 2 of 8	ENST00000008391.4	NP_758438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2D	ENST00000008391.4	c.413A>T	p.Asp138Val	missense_variant	Exon 2 of 8	1	NM_172238.4	ENSP00000008391.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413A>T (p.D138V) alteration is located in exon 2 (coding exon 2) of the TFAP2D gene. This alteration results from a A to T substitution at nucleotide position 413, causing the aspartic acid (D) at amino acid position 138 to be replaced by a valine (V). 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	0.89
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.83
MutPred		0.49		Loss of disorder (P = 0.0053);
MVP		0.51
MPC		0.54
ClinPred		0.86	D
GERP RS		5.1
Varity_R		0.64
gMVP		0.68

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.

Other links and lift over

hg19: chr6-50683202;