20-56631562-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003222.4(TFAP2C):​c.406G>C​(p.Val136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,531,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: TFAP2C NM_003222.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06392196).
• BS2: High AC in GnomAd4 at 41 AD gene.

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>C	p.Val136Leu	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>C	p.Val136Leu	missense	Exon 2 of 7	ENSP00000201031.2	Q92754-1
	TFAP2C	ENST00000882953.1		c.406G>C	p.Val136Leu	missense	Exon 2 of 7	ENSP00000553012.1
	TFAP2C	ENST00000416606.1	TSL:3	c.*15G>C		downstream_gene	N/A	ENSP00000390857.1	A2A2R7

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000102 AC: 13 AN: 126910 AF XY: 0.0000713

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000150

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000484 AC: 668 AN: 1378810 Hom.: 1 Cov.: 34 AF XY: 0.000461 AC XY: 314 AN XY: 680734

African (AFR) AF: 0.0000988 AC: 3 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: 0.0000128 AC: 1 AN: 78036

European-Finnish (FIN) AF: 0.0000280 AC: 1 AN: 35714

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

European-Non Finnish (NFE) AF: 0.000579 AC: 624 AN: 1077798

Other (OTH) AF: 0.000678 AC: 39 AN: 57486

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74448

African (AFR) AF: 0.000216 AC: 9 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000428 Hom.: 0

Bravo AF: 0.000272

ExAC AF: 0.0000693 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.66
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.064	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.0030	B
Vest4		0.14
MutPred		0.21		Loss of glycosylation at S137 (P = 0.0934)
MVP		0.39
MPC		0.89
ClinPred		0.0074	T
GERP RS		0.66
Varity_R		0.049
gMVP		0.086
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;