6-50715519-T-A

Variant names:

• chr6-50715519-T-A
• rs765008227
• NM_172238.4:c.443T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_172238.4(TFAP2D):​c.443T>A​(p.Met148Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,824 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M148T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TFAP2D NM_172238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2D	NM_172238.4	MANE Select	c.443T>A	p.Met148Lys	missense	Exon 2 of 8	NP_758438.2	Q7Z6R9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2D	ENST00000008391.4	TSL:1 MANE Select	c.443T>A	p.Met148Lys	missense	Exon 2 of 8	ENSP00000008391.4	Q7Z6R9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460824 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726762

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.0	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.71
Sift	Benign	0.30	T
Sift4G	Benign	0.94	T
Polyphen		0.46	P
Vest4		0.86
MutPred		0.47		Gain of ubiquitination at M148 (P = 0.006)
MVP		0.26
MPC		0.59
ClinPred		0.80	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.71
Mutation Taster		=46/54	disease causing

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: rs765008227; hg19: chr6-50683232;