20-56631562-G-A

Variant names:

• chr20-56631562-G-A
• rs771721373
• NM_003222.4:c.406G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003222.4(TFAP2C):​c.406G>A​(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,378,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. V136L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TFAP2C NM_003222.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

Genes affected

TFAP2C (HGNC:11744): (transcription factor AP-2 gamma) The protein encoded by this gene is a sequence-specific DNA-binding transcription factor involved in the activation of several developmental genes. The encoded protein can act as either a homodimer or heterodimer with other family members and is induced during retinoic acid-mediated differentiation. It plays a role in the development of the eyes, face, body wall, limbs, and neural tube. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10783103).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003222.4. 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
	TFAP2C	NM_003222.4	MANE Select	c.406G>A	p.Val136Met	missense	Exon 2 of 7	NP_003213.1	Q92754-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2C	ENST00000201031.3	TSL:1 MANE Select	c.406G>A	p.Val136Met	missense	Exon 2 of 7	ENSP00000201031.2	Q92754-1
	TFAP2C	ENST00000882953.1		c.406G>A	p.Val136Met	missense	Exon 2 of 7	ENSP00000553012.1
	TFAP2C	ENST00000416606.1	TSL:3	c.*15G>A		downstream_gene	N/A	ENSP00000390857.1	A2A2R7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378812 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 680736

African (AFR) AF: 0.00 AC: 0 AN: 30374

American (AMR) AF: 0.00 AC: 0 AN: 35084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24808

East Asian (EAS) AF: 0.00 AC: 0 AN: 35044

South Asian (SAS) AF: 0.00 AC: 0 AN: 78036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4466

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077800

Other (OTH) AF: 0.00 AC: 0 AN: 57486

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Benign	-0.14	N
PhyloP100		1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.23	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.094
MutPred		0.27		Gain of catalytic residue at V136 (P = 0.0262)
MVP		0.34
MPC		0.90
ClinPred		0.13	T
GERP RS		0.66
Varity_R		0.043
gMVP		0.087
Mutation Taster		=289/11	polymorphism

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: rs771721373; hg19: chr20-55206618;