20-56631503-C-G

Variant names:

• chr20-56631503-C-G
• rs1987489958
• NM_003222.4:c.347C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003222.4(TFAP2C):​c.347C>G​(p.Ser116Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,354,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TFAP2C NM_003222.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23281792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2C	NM_003222.4	c.347C>G	p.Ser116Trp	missense_variant	Exon 2 of 7	ENST00000201031.3	NP_003213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2C	ENST00000201031.3	c.347C>G	p.Ser116Trp	missense_variant	Exon 2 of 7	1	NM_003222.4	ENSP00000201031.2
TFAP2C	ENST00000416606.1	c.311C>G	p.Ser104Trp	missense_variant	Exon 2 of 2	3		ENSP00000390857.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1354062 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 667278

Gnomad4 AFR exome AF: 0.0000355

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.38e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347C>G (p.S116W) alteration is located in exon 2 (coding exon 2) of the TFAP2C gene. This alteration results from a C to G substitution at nucleotide position 347, causing the serine (S) at amino acid position 116 to be replaced by a tryptophan (W). 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	Benign	0.30
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.95	P;.
Vest4		0.47
MutPred		0.35		Gain of catalytic residue at S116 (P = 0.0053);.;
MVP		0.61
MPC		1.6
ClinPred		0.51	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs1987489958; hg19: chr20-55206559;