6-50751309-A-T

Variant names:

• chr6-50751309-A-T
• rs772703723
• NM_172238.4:c.1124A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_172238.4(TFAP2D):​c.1124A>T​(p.His375Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. H375R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFAP2D NM_172238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

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.1124A>T	p.His375Leu	missense	Exon 7 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.1124A>T	p.His375Leu	missense	Exon 7 of 8	ENSP00000008391.4	Q7Z6R9
	TFAP2D	ENST00000492804.1	TSL:5	n.*35A>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Benign	0.17	T
Sift4G	Benign	0.26	T
Polyphen		0.62	P
Vest4		0.77
MutPred		0.69		Gain of helix (P = 0.0496)
MVP		0.12
MPC		1.2
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.36
gMVP		0.77
Mutation Taster		=6/94	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: rs772703723; hg19: chr6-50719022;